JP6671541B2 - Heterocyclic compounds useful as antibacterial agents and methods for their production - Google Patents

Description

  The present invention relates to the field of medicinal chemistry, and more particularly to the development of antibacterial compounds effective against bacteria, viruses, fungi and protozoa, including a range of Gram-negative and Gram-positive pathogens. The present disclosure relates to compounds of formula I, stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms thereof. And pharmaceutically active derivatives, and pharmaceutical compositions containing them as active ingredients. The present disclosure further relates to the synthesis and characterization of such compounds that exhibit high antimicrobial activity.

  The compounds of the present disclosure are useful as medicaments for the treatment, prevention or control of diseases and conditions mediated by microorganisms and for use in the manufacture of such medicaments. The present invention also provides evidence for treating infections caused by microorganisms.

  There are global alarming issues regarding the rapid evolution of antibiotic resistance that can result in strains for which no effective antimicrobial is present. In general, bacterial pathogens can be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds that have effective activity against both Gram-positive and Gram-negative pathogens are considered to have broad activity. Current antimicrobial agents used to treat and prevent bacterial infections have been found to have limited effectiveness. Furthermore, it has improved efficacy against bacterial infections that are resistant to treatment with currently available antibiotics, or has less potential to develop resistance that is selective for target microorganisms, New compounds with strong antibacterial activity need to be constantly identified.

International Publication No. 2008126024

Remington's Pharmaceutical Sciences (21st edition, 2005, University of the sciences in Philadelphia, Lippincott William & Wilkins) Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 Advanced Organic Chemistry by Jerry March and Michael Smith, 5th Edition, published by John Wiley & Sons, 2001 T.W.Green, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991

  From the foregoing, it is clear that compounds used in the state of the art to treat and prevent bacterial infections have been found to have limited efficacy. In addition, they have reduced potential for developing resistance, improved efficacy against bacterial infections that are resistant to treatment with currently available antibiotics, or have unexpected There is a constant need to identify new compounds with improved selectivity and improved antimicrobial activity.

  The present disclosure is based on the surprising discovery that compounds of formula I (see below) exhibit advantageous antimicrobial properties. Accordingly, the present disclosure provides compounds of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. provide
Wherein R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, each of which is unsubstituted or halogen, hydroxy, , Substituted with 1-3 groups independently selected from amino, oxetane, -OC _1-6 alkyl, C _3-6 cycloalkylamino, C _1-6 alkylamino or di (C _1-6 alkyl) amino Has been
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} from the group consisting of alkyl and -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----), when represents a non-binding, dotted line (----) represents either bound or unbound, W is O,
Ring A is an unsaturated or partially unsaturated, 3- to 10-membered substituted or unsubstituted heteroaryl optionally having up to 3 heteroatoms independently selected from O, N, NH or S Selected from the group consisting of ring systems].

  The present disclosure further provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt thereof, for use in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa. And salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  The present disclosure further provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt thereof, in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa, It relates to the use of complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  The present disclosure further provides a compound of formula I, or a stereoisomer, a pharmaceutical thereof, for use in the treatment of a disease or condition in a patient caused by a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa. And salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  The present disclosure further provides a compound of Formula I, or a stereoisomer thereof, in the treatment of a disease or condition in a patient caused by a microorganism selected from the group consisting of bacteria, viruses, fungi, and protozoa, It relates to the use of salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. The patient is typically a mammal, preferably a human.

  The present disclosure is further directed to a method of treating a disease or condition in a patient caused by a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa, wherein the compound comprises a compound of Formula I, or a stereoisomer thereof. Administering pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. About the method.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active It relates to a composition comprising the form and the pharmaceutically active derivative together with a carrier.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active It relates to a pharmaceutical composition comprising a form and a pharmaceutically active derivative, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active The present invention relates to forms and to methods for preparing pharmaceutically active derivatives.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active It relates to a method of preparing a composition comprising the form and the pharmaceutically active derivative together with a carrier.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active A method for preparing a pharmaceutical composition comprising a form and a pharmaceutically active derivative, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

  These and other features, aspects, and advantages of the present inventive subject matter will be better understood by reference to the following description. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify critical or essential features of the present disclosure, nor is it intended to be used to limit the scope of the subject matter.

  The detailed description is described by reference to the accompanying figures. In the figures, the left-most digit of a reference number identifies the figure in which the reference number first appears. The same numbers are used throughout the figures to reference like features and components.

FIG. 4 shows the MIC ₉₀ of Example 14 for clinical strains of the four major Gram-negative bacterial species, according to one embodiment of the present disclosure. FIG. 13 shows the in vivo efficacy of Example 13 in a mouse thigh infection model according to one embodiment of the present disclosure.

  Those skilled in the art will recognize that changes and modifications may be made to the present disclosure other than those specifically described. It is to be understood that the present disclosure includes all such changes and modifications. The present disclosure also includes any such steps, features, compositions and compounds, referred to or indicated herein, individually or collectively, and any or more of such steps or features. Including any and all combinations of

Definitions For convenience, before further description of the present disclosure, certain terms used in the specification and examples are collected here. These definitions should be interpreted as understood by those skilled in the art in light of the remainder of the disclosure. The terms used herein have the meanings recognized and known to those skilled in the art, but for convenience, for completeness, certain terms and their meanings are set forth below.

  The articles “a”, “an” and “the” are used to refer to one or more (ie, to at least one) of the grammatical object of the article.

  The terms "comprise" and "comprising" are used in an inclusive, broad sense and mean that additional elements may be included. Throughout this specification, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are used to refer to the stated element or step or element. Or a group of steps, but is understood to imply that it does not exclude any other element or step or group of elements or steps.

  The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

  In the structural formulas shown throughout the present disclosure herein, the following terms have the indicated meanings unless specifically stated otherwise.

In this specification, the prefix C _{x to y} used in terms such as C _{x to y} alkyl such as (wherein, x and y are integers), the numerical range of carbon atoms present in the group shows, for example, the C _{1 to 6} alkyl, C ₁ alkyl (methyl), C ₂ alkyl (ethyl), C ₃ alkyl (propyl and isopropyl) and C ₄ alkyl (butyl, 1-methylpropyl, 2-methylpropyl , And t-butyl). Unless specifically stated, the bonding atom of the group may be any suitable atom of the group, for example, propyl includes prop-1-yl and prop-2-yl.

  The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 to 10 carbon atoms. This term is exemplified by groups such as n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl and the like. Those groups may be optionally substituted.

  The term "alkylene" refers to a diradical branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms. This term is exemplified by groups such as methylene, ethylene, propylene, butylene, hexylene, and the like. Those groups may be optionally substituted. Representative substituted alkylene groups include hydroxyl-substituted alkylene.

  The term `` alkenyl '' preferably has two, three, four, five or six carbon atoms and has one, two or three double bonds (vinyl), preferably one Refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having a double bond of Those groups may be optionally substituted.

  The term "cycloalkyl" refers to a carbocyclic group of 3 to 12 carbon atoms having a single cyclic ring or multiple fused rings that may be partially unsaturated. Such cycloalkyl groups include, for example, a single ring structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, etc., or multiple ring structures or carbocyclic groups to which an aryl group is fused, For example, indane and the like are included. Those groups may be optionally substituted.

  The terms "alkoxyl" or "alkoxy" refer to an alkyl group, as defined above, to which an oxygen radical is attached. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, a substituent of an alkyl that makes the alkyl an ether is an alkoxyl or similar to an alkoxyl, as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl. I have.

  “Halo” or “halogen,” alone or in combination with any other term, means a halogen, such as chloro (Cl), fluoro (F), bromo (Br), and iodo (I).

  The term `` heteroaryl '' refers to a heteroaromatic of 3 to 10 carbon atoms having a single ring (e.g., pyridine) or multiple rings (e.g., isoquinoline) or multiple condensed (fused) rings. Refers to a group carbocyclic group. Preferred heteroaryls include thiophene, pyrazole, thiazole, pyridine and the like. Those groups may be optionally substituted.

  As used herein, the term "substituted" is intended to include all acceptable substituents on organic compounds. In one broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds . Exemplary substituents include, for example, those described herein above. Acceptable substituents can be one or more, the same or different, for appropriate organic compounds. For purposes of this disclosure, a heteroatom such as nitrogen can have a hydrogen substituent and / or any acceptable substituent of an organic compound described herein that satisfies the valence of the heteroatom.

  The term "effective amount" means an amount of a compound or composition that is sufficient to significantly positively modify the condition and / or condition being treated (eg, resulting in a positive clinical response). An effective amount of the active ingredient for use in the pharmaceutical composition will depend on the particular condition to be treated, the severity of the condition, the duration of the treatment, the nature of the combination therapy, the particular active ingredient used and the pharmaceutically acceptable salt utilized. It will depend on the particular excipient / carrier, the route of administration and similar factors contained in the knowledge and expertise of the attending physician.

  The compounds described herein may contain one or more chiral centers and / or double bonds, and are therefore stereoisomers, e.g., double bond isomers (i.e., geometric isomers), It can exist as regioisomers, enantiomers or diastereomers. Thus, the chemical structures depicted herein are representative of stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure or diastereomeric) of the exemplified or identified compounds. ) And all possible enantiomers and stereoisomers, including mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be resolved into their constituent enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in several tautomeric forms, including enol forms, keto forms and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds illustrated or identified.

  The term "pharmaceutically acceptable" is used in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, within the scope of sound medical judgment. Refers to a compound, material, composition, and / or dosage form that is appropriate for

  “Pharmaceutically acceptable salt” includes salts containing a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid and nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid , Malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides and organic bases, e.g., alkylamines, arylalkylamines, and heterocyclic amines. It is.

  In many cases, the compounds discussed herein are those that have been named and / or checked using the ACD / Name by ACD / Labs® and / or the Electronic Lab Notebook by CambridgeSoft®. It is possible.

  The term "polymorph" refers to a crystalline system of the same molecule, wherein different polymorphs are different as a result of the arrangement or configuration of the molecule in a crystal lattice, e.g., melting temperature, heat of fusion, solubility, dissolution rate and / or vibrational spectrum. Etc. can have different physical properties.

  The term "solvate" as used herein refers to a crystalline form of a substance containing a solvent.

  The term "hydrate" refers to a solvate wherein the solvent is water.

  The term "drug-sensitive bacterium" as used herein is a bacterium that cannot survive exposure to at least one drug.

  The present disclosure provides compounds of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C ₃ -C ₆ cycloalkyl, each of which is unsubstituted or halogen, hydroxy, amino, Oxetane, -OC _1-6 alkyl, C _3-6 cycloalkylamino, C _1-6 alkylamino or di (C _1-6 alkyl) amino substituted with 1-3 groups independently selected. ,
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, C _{1 to 6} alkyl, and from the group consisting of -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----), when represents a non-binding, dotted line (----) represents either bound or unbound, W is O,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, wherein alkyl is fluorine, hydroxy, amino, oxetane, —OC ₁ alkyl _Is optionally substituted with 1-3 groups independently selected from _C3-6 cycloalkylamino, _C1-2 alkylamino, or di ( _C1-2 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, a cyano, -OC _{1 to 6} alkyl, -C _{1 to 6} from the group consisting of alkyl and -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----), when represents a non-binding, dotted line (----) represents either bound or unbound, W is O,
Ring A is

Selected from the group consisting of:

According to one embodiment, the present disclosure relates to a compound of the formula: wherein Z ₂ is C _1-6 alkylene, Z ₁ is NH, or Z ₂ is NH, Z ₁ is C _1-6 alkylene. Or a C _1-6 hydroxyalkylene, a compound of formula I, or a stereoisomer thereof, a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture thereof. , Optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, wherein alkyl is fluorine, hydroxy, amino, oxetane, —OC ₁ alkyl _Is optionally substituted with 1-3 groups independently selected from _C3-6 cycloalkylamino, _C1-2 alkylamino, or di ( _C1-2 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC ₁ alkyl, O, or CR ₃ R ₄ ;
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, fluorine, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, fluorine, chlorine, cyano, -OCH _3, is selected from -OCF _3, OCHF _2, and the group consisting of C ₁ alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, cyano, -OCH _3, is selected from the group consisting of -OCHF _2, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, wherein alkyl is halogen, hydroxy, amino, oxetane, —OC _{1- 6} alkyl, C _3-6 cycloalkylamino, C _1-6 alkylamino, or optionally substituted with 1-3 groups independently selected from di (C _1-6 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, is selected from halogen, cyano, C _{1 to 6} alkyl, -OC _{1 to 6} from the group consisting of alkyl and -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C ₃ -C ₆ cycloalkyl, wherein alkyl is fluorine, hydroxy, amino, oxetane, —OC ₁ alkyl, which is optionally substituted with C ₃ -C ₆ cycloalkylamino, C _{1 to 2} alkylamino, or di (C _{1 to 2} alkyl) 1-3 groups selected from amino independently,
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, fluorine, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, fluorine, chlorine, cyano, -OCH _3, is selected from -OCF _3, OCHF _2, and the group consisting of C ₁ alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, cyano, selected from the group consisting of -OCH _3, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, wherein alkyl is fluorine, —OC ₁ alkyl, amino, hydroxy, oxetane, C ₃ -C ₆ cycloalkylamino, C _1-2 Optionally substituted with 1-3 groups independently selected from alkylamino, or di (C _1-2 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, amino, and hydroxyl;
X is O, -NC ₁ alkyl, or CR ₃ R ₄ ;
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, fluorine, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, fluorine, chlorine, is cyano, -OC ₁ alkyl, -OCF _3, OCHF _2, and the group consisting of C ₁ alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is selected from the group consisting of hydrogen, fluorine, cyano, —OC ₁ alkyl, and —OCF ₃ ;
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. [Where,
R ₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, wherein alkyl is fluorine, —OC ₁ alkyl, hydroxy, amino, oxetane, C _3-6 cycloalkylamino, C _1-2 alkyl Optionally substituted with 1-3 groups independently selected from amino or di (C _1-2 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, amino, and hydroxyl;
X is CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, fluorine, chlorine, cyano, -OCH _3, is selected from the group consisting of -CF _3, OCHF _2, and C ₁ alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, cyano, -OCH _3, is selected from the group consisting of -OCHF _2, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. [Where,
R ₁ is C ₁ alkyl, wherein alkyl is independently selected from fluorine, —OC ₁ alkyl, hydroxy, amino, oxetane, C _1-2 alkylamino, or di (C _1-2 alkyl) amino Optionally substituted with one to three groups,
R ₂ is hydrogen;
X is CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, C ₁ alkyl, or cyano;
Y ₂ is CH,
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, cyano, selected from the group consisting of -OCH _3, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of:

According to one embodiment, the present disclosure provides:
R ₁ is C ₂ alkyl, wherein alkyl is independently selected from fluorine, —OC ₁ alkyl, amino, hydroxyl, C _1-2 alkylamino, or di (C _1-2 alkyl) amino Optionally substituted with 1-3 groups,
R ₂ is hydrogen;
X is O or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is selected from the group consisting of hydrogen, C ₁ alkyl, and cyano;
Y ₂ is CH,
Y ₃ is N or CR ₆ ,
R ₆ is selected from the group consisting of hydrogen, fluorine, cyano, —OCH ₃ , OCHF ₂ and —OCF ₃ ;
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of
Compounds of Formula I, or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically acceptable salts thereof. To derivatives that are active.

According to one embodiment, the present disclosure provides:
R ₁ is C ₁ alkyl, wherein alkyl is independently selected from fluorine, —OC ₁ alkyl, amino, hydroxyl, C _1-2 alkylamino, or di (C _1-2 alkyl) amino Optionally substituted with 1-3 groups,
R ₂ is hydrogen;
X is O,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is selected from the group consisting of hydrogen, C ₁ alkyl, and cyano;
Y ₂ is CH,
Y ₃ is N or CR ₆ ,
R ₆ is selected from the group consisting of hydrogen, fluorine, cyano, —OCH ₃ , OCHF ₂ and —OCF ₃ ;
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of
Compounds of Formula I, or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically acceptable salts thereof. To derivatives that are active.

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.
[Where,
R ₁ is C _1-4 alkyl;
R ₂ is hydrogen;
X is O or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen;
Y ₂ is CH,
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, cyano, selected from the group consisting of -OCH _3, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of:

  According to one embodiment, the present disclosure provides a compound of formula I

Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. [Where,
R ₁ is selected from the group consisting of methyl, ethyl, and isopropyl;
R ₂ is hydrogen;
X is CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, CH ₃ , CN;
Y ₂ is CH,
Y ₃ is CR ₆ ;
R ₆ is hydrogen, fluorine, cyano, —OCH ₃ , and —OCF ₃ ;
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of:

According to one embodiment, the present disclosure provides:
R ₁ is selected from the group consisting of C _1-3 alkyl, wherein alkyl is fluorine, —OC ₁ alkyl, amino, hydroxy, C _1-2 alkylamino, or di (C _1-2 alkyl) amino Optionally substituted with 1-3 groups independently selected from
R ₂ is hydrogen;
X is CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is selected from the group consisting of hydrogen, CH ₃ , and CN;
Y ₂ is CH,
Y ₃ is N or CR ₆ ,
R ₆ is v, hydrogen, fluorine, cyano, selected from the group consisting of -OCH _3, and -OCF _3,
When Z ₂ vCH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is H ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ,
n is 1 or 2,
W is O when the dotted line (----) represents either a bond or a non-bond,
Ring A is

Selected from the group consisting of
Compounds of Formula I, or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically acceptable salts thereof. To derivatives that are active.

According to one embodiment, the present disclosure provides:
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C ₃ -C ₆ cycloalkyl, wherein alkyl is fluorine, hydroxy, amino, oxetane, —OC ₁ alkyl, which is optionally substituted with C ₃ -C ₆ cycloalkylamino, C _{1 to 2} alkylamino, or di (C _{1 to 2} alkyl) 1-3 groups selected from amino independently,
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, fluorine, a cyano, -OC _{1 to 6} alkyl, -C _{1 to 6} from the group consisting of alkyl and -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, W, when the dotted line (----) represents either bound or unbound, is O,
Ring A is

Selected from the group consisting of
Compounds of Formula I, or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically acceptable salts thereof. To derivatives that are active.

According to one embodiment, the present disclosure, wherein, X _{is, NH, -N (CH 3)} , O, CH 2, CH-F, in CH-CH _3, CF ₂ or C (CH _{3) 2} Certain compounds of Formula I, or stereoisomers thereof, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms thereof, and It relates to pharmaceutically active derivatives.

According to one embodiment, the present disclosure, wherein, X is O, -CH, C (F) 2, or C- a (CH _{3) 2,} the compound of formula I, or a stereoisomer, pharmaceutically And salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

According to one embodiment, the present disclosure, the salts wherein, X is -CH _2, or C- a (CH _{3) 2,} the compound of Formula I, or a stereoisomer, a pharmaceutically acceptable , Complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides a compound of formula I, wherein R ₂ is selected from H, hydroxy or amino, or a stereoisomer thereof, pharmaceutically acceptable salt, complex, water It relates to solvates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides a compound of formula I, wherein R ₂ is H, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate thereof. , Tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides a compound of formula I, wherein Z ₁ and Z ₂ are independently selected from —NH—, —CH ₂ , or CH ₂ CH ₂ , or a stereoisomer thereof. And pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

According to one embodiment, the present disclosure provides a compound of formula I, wherein Y ₂ is N or CH, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvent thereof. It relates to the solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides a compound of formula I, wherein Y ₂ is CH, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate thereof. , Tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides that, wherein Y ₁ is N, CH, CF, CCl, C-CN, C-OCH ₃ , C-OCF ₃ , C-OCHF ₂ , or C-CH ₃ Or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form thereof, And pharmaceutically active derivatives.

According to one embodiment, the present disclosure relates to a compound of formula I, wherein Y ₁ is CH, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate thereof. , Tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure, wherein, Y ₃ is N, -CH, -CF, -C ( CN), - C (OCH 3), - C (OCF 3), or -C (OCHF ₂ ) is a compound of formula I, or a stereoisomer thereof, a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active And pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides a compound of formula I, wherein Y ₃ is -CH, or -CF, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate thereof. , Solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I, wherein n is 1 or 2, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate thereof. , Tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

According to one embodiment, the present disclosure provides:
6- (5- (2-(((1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-(((6-fluoro-1,3,3-trimethyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H -Pyrido [3,2-b] [1,4] oxazin-3 (4H) -one,
5- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotino Nitrile,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (3-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1),
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -one,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) -2-hydroxyethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-((2- (5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-4-yl) ethyl) amino) ethyl) -2-oxo Oxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, and
6- (5- (3-(((6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridin-7-yl) methyl) amino) propyl ) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, a compound of formula I, or a compound thereof. It relates to stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: Mixtures, optically active forms and methods for preparing pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer thereof, for use in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa. , Pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt thereof, for use in killing or inhibiting the growth of Gram-positive and Gram-negative bacteria. , Complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure relates to Escherichia coli, Salmonella typhi, Salmonella paratyphi, Salmonella typhimurium, Salmonella enteritidis. Shigella dysenteriae, Shigella flexneri, Shigella boyd, Shigella boydii, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermis Streptococcus pneumoniae, Streptococcus pygenes, Stenotrophomonas maltophilia, Haemophilus influenza, Klebsiella pneumoniae, Legionella pneumoniae Mycoplasma pneumoniae, reed Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter lwoffi, Burkholderia cephaeumia, Burkholderia cepacia um Clostridium difficili, Pseudomonas aeruginosa, Enterobacter aerogenes, Enterobacter cloacae, Moraxella catarrhalis, Enterococcus faecium, Enterococcus faecium E. faecalis (Enterococcus faecalis), Enterococcus faeciu (Enterococcus faeciu), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Neisseria meningitides, or those A compound of formula I, or a stereoisomer, pharmaceutically acceptable salt thereof, for use in killing or inhibiting the growth of drug-sensitive and drug-resistant bacteria selected from the group consisting of: It relates to complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically, thereof, for killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, viruses, fungi and protozoa. It relates to the use of acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer thereof, for use in the treatment of a disease or condition in a patient caused by a microorganism selected from the group consisting of a gram negative pathogen and a gram positive pathogen. It relates to isomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  According to one embodiment, the present disclosure relates to a compound of Formula I, or a stereoisomer thereof, in the treatment of a disease or condition in a patient caused by a microorganism selected from the group consisting of a Gram-negative pathogen and a Gram-positive pathogen. It relates to the use of chemically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. The patient is typically a mammal, preferably a human.

  According to one embodiment, the present disclosure provides a method of treating a disease or condition in a patient caused by a microorganism selected from the group consisting of a Gram-negative pathogen and a Gram-positive pathogen, wherein the compound comprises a compound of Formula I, Or its stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. A method comprising the step of administering.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer thereof, for use as a medicament. It relates to sex forms, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex thereof, for use in the preparation of a medicament for inhibiting microbial growth. It relates to hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex thereof, for use in the preparation of a medicament for inhibiting bacterial growth. It relates to hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure relates to a medicament comprising a compound of formula I, or an addition salt of a compound of formula I with a pharmaceutically acceptable acid or base. These medicaments are useful in therapy, especially for bacterial infections caused by both drug-sensitive and drug-resistant bacteria, including quinolone resistance, belonging to Gram-positive and Gram-negative species, especially E. coli, Staphylococcus aureus, Klebsiella pneumoniae, It has been found that it can be used in the treatment of bacterial infections caused by Acinetobacter baumannii, Pseudomonas aeruginosa, Clostridium difficile, Neisseria gonorrhea, and E. faecalis.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer thereof, in the manufacture of a medicament for the treatment of an infection caused by a bacterial species in a warm-blooded animal, such as a human, It relates to the use of acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex thereof, in the manufacture of a medicament for providing an antimicrobial effect in a warm-blooded animal, for example, a human. , Hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and the use of pharmaceutically active derivatives.

  According to one embodiment, the present disclosure provides a method for treating an infection caused by a bacterial species in a warm-blooded animal, such as a human, comprising administering to said animal an effective amount of a compound of Formula I, or a pharmaceutical agent. And the step of administering a pharmaceutically acceptable salt thereof.

  According to one embodiment, the present disclosure provides a method for providing an antimicrobial effect in a warm-blooded animal, for example, a human, wherein the animal is provided with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. And administering to the subject.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing a bacterial infection in a warm-blooded animal, eg, a human.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a pharmaceutically acceptable carrier, for therapeutic and prophylactic treatment of mammals, including humans, particularly in the treatment of bacterial infections caused by bacterial species. With regard to the acceptable salts thereof, it is usually formulated as a pharmaceutical composition according to standard pharmaceutical practice.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: The invention relates to a pharmaceutical composition comprising a mixture, an optically active form and a pharmaceutically active derivative, and at least one pharmaceutically acceptable carrier, diluent or excipient.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer thereof, in the manufacture of a medicament for the treatment of a bacterial infection caused by a bacterial species in a warm-blooded animal, for example a human. The invention relates to the use of a pharmaceutical composition comprising a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form and pharmaceutically active derivative thereof.

  According to one embodiment, the present disclosure provides a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex thereof, in the manufacture of a medicament for providing an antimicrobial effect in a warm-blooded animal, for example, a human. , Hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: It relates to a pharmaceutical composition comprising the mixture, the optically active form and the pharmaceutically active derivative in combination with at least one antibiotic together with a pharmaceutically acceptable carrier.

  According to one embodiment, the present disclosure provides a method for treating an infection caused by a bacterial species in a warm-blooded animal, such as a human, wherein the animal is provided with a compound of Formula I, or a stereoisomer thereof. An effective amount of a composition comprising a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form and pharmaceutically active derivative thereof. And administering a substance.

  According to one embodiment, the present disclosure is a method for producing an antimicrobial effect in a warm-blooded animal, such as a human, wherein the animal has a compound of Formula I, or a stereoisomer thereof, pharmaceutically acceptable. Administering an effective amount of the composition, including salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof. About the method.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: It relates to a pharmaceutical composition comprising the mixture, the optically active form and the pharmaceutically active derivative together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: The invention relates to a pharmaceutical composition comprising a mixture, an optically active form and a pharmaceutically active derivative, and a pharmaceutically acceptable diluent or carrier.

  According to one embodiment, the present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemate thereof: The invention relates to a composition comprising a mixture, an optically active form and a pharmaceutically active derivative, and a carrier.

  The term "pharmaceutically acceptable" is used in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, within the scope of sound medical judgment. Including compounds, materials, compositions, and / or dosage forms that are suitable for

  Compounds of formula I may form stable pharmaceutically acceptable acid or base salts, in which case it may be appropriate to administer the compound as a salt. Examples of acid addition salts are acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citric acid Acid salt, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, Hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate Salt, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, Stearates, succinates, sulfamic acids, sulfanilates, sulfates, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts are ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine and N10 methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine and the like. Also, basic nitrogen-containing groups are lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate; diamyl sulfate; long-chain halides For example, decyl halides, lauryl halides, myristyl halides and stearyl halides; arylalkyl halides such as benzyl bromide. Non-toxic physiologically acceptable salts are preferred, but other salts may be useful, for example, in isolating or purifying the product.

  The salt may be prepared by conventional means, e.g., by converting the free base form of the product to one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo. It can be formed by reacting, by lyophilization, or by exchanging the existing salt anion for another anion on a suitable ion exchange resin.

  The compositions of the present disclosure can be used for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., creams) Ointment, gel, or aqueous or oily solution or suspension), inhaled administration (e.g., as a finely divided powder or liquid aerosol), insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., intravenous) As a sterile aqueous or oily solution for subcutaneous, intramuscular or intramuscular administration, or as a suppository for rectal administration).

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active It relates to a method of preparing a composition comprising the form and the pharmaceutically active derivative together with a carrier.

  The present disclosure relates to a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active A method for preparing a pharmaceutical composition comprising a form and a pharmaceutically active derivative, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

  The compositions of the present disclosure can be obtained by conventional procedures, using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

  Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents, such as corn starch or alginic acid; Lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate; and antioxidants, such as ascorbic acid. The tablet formulations may be uncoated or, in any case, to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance. Can also be coated using conventional coatings or procedures well known in the art.

  Compositions for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or wherein the active ingredient is water or oil, For example, it can be present as a soft gelatin capsule mixed with peanut oil, liquid paraffin or olive oil.

  Aqueous suspensions generally contain the active ingredient in micronized form or in the form of nanoparticles or micronized particles, one or more suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, Polyvinyl-pyrrolidone, tragacanth gum and gum acacia; dispersing or wetting agents such as lecithin, or the condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or the condensation of ethylene oxide with long chain fatty alcohols Products, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide and long chain fat Condensation products of aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or partial esters derived from ethylene oxide and fatty acids and hexitol anhydride Together with a condensation product of, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or propyl p-hydroxybenzoate; antioxidants, such as ascorbic acid); coloring agents; flavoring agents; and / or sweetening agents. For example, sucrose, saccharin or aspartame.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparing an aqueous suspension by adding water are generally active together with dispersing or wetting agents, suspending agents and one or more preservatives. Contains ingredients. Suitable dispersing or wetting agents and suspending agents are exemplified by those already listed. Additional excipients, for example sweetening, flavoring and coloring agents, may be present.

  The pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example, olive or peanut oil, or a mineral oil, for example, liquid paraffin, or a mixture of any of these. Suitable emulsifiers include, for example, naturally occurring gums such as acacia or tragacanth gum, naturally occurring phosphatides such as soybeans, lecithin, esters or partial esters from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate), and the moieties It can be a condensation product of an ester and ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening, flavoring and preservative agents.

  Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, aspartame or sucrose, and can also contain demulcents, preservatives, flavoring and / or coloring agents.

  The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be one of the suitable dispersing or wetting agents and suspending agents listed above according to known procedures. Or it may be formulated using more than one. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.

  Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol prepared to disperse the active ingredient, either as a finely divided solid or as an aerosol containing droplets. Conventional aerosol propellants, such as volatile fluorinated hydrocarbons or hydrocarbons, can be used, and the aerosol device is conveniently prepared to disperse the metered active ingredient.

  Compositions for administration can also be formulated as liposome preparations. Liposomal preparations include liposomes that penetrate the cell or stratum corneum of interest and fuse with the cell membrane, so that the contents of the liposome can be delivered to the cells. Other suitable formulations can use niosomes. Niosomes are lipid vesicles, like liposomes, whose membranes consist primarily of nonoinic lipids, some forms of which are effective at transporting compounds through the stratum corneum.

  Compositions for administration can also be formulated as a depot preparation, which can be administered by implantation or intramuscular injection. The composition can be formulated with a suitable polymeric or hydrophobic material (as an emulsion in an acceptable oil), an ion exchange resin, or a sparingly soluble derivative.

  The compounds of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems.

  See Remington's Pharmaceutical Sciences (21st Edition, 2005, University of the Sciences in Philadelphia, Lippincott William & Wilkins) for more information on formulation, drug delivery, and processing techniques.

  The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, formulations intended for oral administration to humans generally contain, for example, 0.5 mg to 4 g of a vehicle, formulated with a suitable and convenient amount of excipient which can vary from about 5 to about 98 weight percent of the total composition. Contains active drug. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For additional information on routes of administration and dosing regimens, see Comprehensive Medicinal Chemistry Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 and Remington's Pharmaceutical Sciences (21st Edition, 2005, University). of the sciences in Philadelphia, Lippincott William & Wilkins).

  As noted above, the magnitude of a dosage required for the therapeutic or prophylactic treatment of a particular condition will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably, a daily dose in the range of 1-25mg / kg is employed. Thus, the optimal dosage may be determined by the attending physician in treating any particular patient.

  Any of the pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features referred to herein apply any of the alternative aspects of the compounds of the present disclosure described herein. .

  The compounds disclosed herein can be applied as a sole treatment, or can include, in addition to the compounds of the disclosure, one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. If the administration occurs over time or separately, the administration of the second component should not be delayed, eg, so as not to lose the beneficial effects of the combination. Suitable classes and substances may be selected from one or more of the following: i) other antimicrobial agents, such as microlides, such as erythromycin, azithromycin or clarithromycin; quinolones, such as ciprofloxacin or levofloxacin; β-lactams, such as penicillins, such as amoxicillin or piperacillin; cephalosporins, such as ceftriaxone or Ceftazidime; carbapenems such as meropenem or imipenem; aminoglycosides such as gentamicin or tobramycin; or oxazolidinone; and / or ii) anti-infectives such as antifungal triazoles such as amphotericin; and / or iii) biological protein therapeutics E.g., antibodies, cytokines, bactericidal / permeability-enhancing protein (BPI) products; and / or iv) one or more useful for treating Mycobacterium tuberculosis Antibacterial agents such as rifampicin, isoniazid, pyrazinamide (pyrazinamide), ethambutol, quinolones, for example Moxifloxacin or gatifloxacin, one or more, and / or v) efflux pump inhibitors streptomycin.

  According to one embodiment, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof, and i) one or more additional antimicrobial agents; and / or ii) one or more antimicrobial agents. Infectious agents; and / or iii) biological protein therapeutics such as antibodies, cytokines, bactericidal / permeability-enhancing protein (BPI) products; iv) pulmonary tuberculosis, extrapulmonary tuberculosis, avian infections, Buruli ulcers And / or v) a chemotherapeutic agent selected from one or more efflux pump inhibitors.

  If the starting materials required for the procedure, such as the materials described herein, are not commercially available, they can be produced by procedures selected from standard organic chemistry techniques, which are structurally similar. Or similar to the procedures described above or in the examples.

  Many of the starting materials for the synthetic methods described herein are commercially available and / or widely reported in the scientific literature, or adapted from processes reported in the scientific literature. It is known that they can be produced from commercially available compounds. For further guidance on reaction conditions and reagents, see further Advanced Organic Chemistry by Jerry March and Michael Smith, 5th Edition, published by John Wiley & Sons, 2001.

  It will also be appreciated that in some of the reactions mentioned herein, it may be necessary / desirable to protect any sensitive groups in the compound. If protection is necessary or desirable, methods suitable for such protection will be known to those skilled in the art. In accordance with standard practice (see, e.g., T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991), conventional protecting groups can be used as described herein above.

Abbreviations The following abbreviations are used in the examples and elsewhere in this specification.
TLC-thin layer chromatography,
HPLC-high pressure liquid chromatography,
MPLC-medium pressure liquid chromatography,
NMR-nuclear magnetic resonance spectroscopy,
DMSO-dimethyl sulfoxide,
CDCl ₃ -deuterated chloroform,
MeOD-deuterated methanol, ie D ₃ COD,
MS-mass spectrometry,
ESP (or ES)-electrospray,
EI-electron impact,
APCI-atmospheric pressure chemical ionization,
THF-tetrahydrofuran,
DCM-dichloromethane,
MeOH-methanol,
DMF-dimethylformamide,
EtOAc-ethyl acetate,
LC / MS-liquid chromatography / mass spectrometry,
h-hour,
min-minute,
d-day,
MTBD-N-methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene,
TFA-trifluoroacetic acid,
v / v-volume / volume ratio,
Boc represents t-butoxycarbonyl,
Cbz represents benzyloxycarbonyl,
Bz represents benzoyl,
atm indicates atmospheric pressure,
rt indicates room temperature,
mg indicates milligram,
g indicates gram,
μL indicates microliter,
mL indicates milliliter,
L indicates liter,
μM indicates micromolar,
mM indicates millimoles,
M represents a mole,
N indicates normal,
nm indicates nanometer.

  The following examples provide details regarding the synthesis, activity and application of the compounds of the present disclosure. It should be understood that the following is merely representative and that the invention is not limited by the details set forth in these examples.

Materials and Methods Evaporation was performed by rotary evaporation in vacuo and work-up procedures were performed after removing residual solids by filtration. Temperatures are stated in ° C. The operation was performed at room temperature, typically in the range 18-26 ° C., without the exclusion of air, unless otherwise specified, or unless the person skilled in the art could work in an inert atmosphere. Compounds were purified using column chromatography (by flash procedure) and performed on Merck's Kieselgel silica (Art.9385) unless otherwise specified. Generally, TLC, HPLC, or LC / MS was performed after the course of the reaction, but the reaction times are given only as examples. Yields are given by way of example only and are not necessarily the maximum achievable. The structure of the final product of the present invention was generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra were generally determined using DMSO d6 unless otherwise specified, using a Bruker DRX 300 spectrometer or a Bruker DRX-400 spectrometer operating at a field intensity of 300 MHz or 400 MHz, respectively. . If the NMR spectrum is complex, record only the diagnostic signal. Chemical shifts are reported in downfield ppm from tetramethylsilane as external standard ( ^* scale) and thus indicate peak multiplicity. s, singlet; d, doublet; dd, doublet doublet; dt, triplet doublet; dm, multiplet doublet; t, triplet, m, multiplet; br , Broad. Fast atom bombardment (FAB) mass spectral data is generally obtained using a platform spectrometer (supplied by Micromass) performed with electrospray, collecting either positive or negative ion data where appropriate Or obtained using an Agilent 1100 series LC / MS with Sedex 75 ELSD, and collected either positive or negative ion data where appropriate. For molecules for which multiple mass spectral peaks are obtained by isotope splitting (eg, when chlorine is present), the main ion with the lowest mass is recorded. Reversed-phase HPLC was performed on an Agilent instrument using a YMC Pack ODS AQ (100 × 20 mmID, particle size S5Å, pore size 12 nm), and each intermediate was purified and assigned to standards required for subsequent steps. The structure was characterized in sufficient detail to confirm its accuracy. Purity was assessed by HPLC, TLC, or NMR, and discrimination was determined by infrared spectroscopy (IR), mass spectroscopy, or NMR spectroscopy as appropriate.

Synthesis of intermediates
Synthesis of 6-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (intermediate I)

Step 1: Synthesis of 6-bromo-2-nitropyridin-3-ol (Ia): 4,6-dichloro-5-meth (metho) 2-nitropyridin-3-ol (20 g, 0.142 mol) in DMF ( To the solution (400 ml) was added N-bromosuccinimide (32.52 g, 0.187 mol) in small portions at 0 ° C. over 5 hours. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was dissolved in ether and the mixture was stirred for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give 6-bromo-2-nitropyridin-3-ol, Ia (40 g, 46%) as a mixture of monobromo and dibromo compounds. LCMS of the crude indicated 46% of the expected monobromo compound, which material was used as is for the next step without further purification. LCMS calculated value of _{C 5 H 3 BrN 2 O 3} , 218.99, obs = 219.2.

Step 2: Synthesis of ethyl 2-((6-bromo-2-nitropyridin-3-yl) oxy) acetate (Ib): 6-bromo-2-nitropyridin-3-ol cooled to 0 ° C., Ia ( To a solution of 40 g (0.182 mol) in acetone (400 ml) was added potassium carbonate (50.41 g, 0.365 mol) and stirred for 5 minutes. Next, ethyl bromoacetate (39.7 g, 0.237 mol) was added slowly and refluxed at 65 ° C. for 12 hours. After the reaction was completed, it was filtered and the filtrate was concentrated in vacuo. The crude was diluted with water and extracted with ethyl acetate (2x600mL). The combined organic layers were washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography with a gradient elution of 20-22% ethyl acetate in petroleum ether to give 2-((6-bromo-2-nitropyridin-3-yl) oxy) ethyl acetate, Ib ( 21g, 75.32%) as a pale yellow solid. C ₉ H ₉ BrN ₂ O ₅ of LCMS calculated value = 305.38, obs = 306.2.

Step 3: Synthesis of 6-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (I): stirred 2-((6-bromo-2-nitropyridine Iron powder (11.51 g, 0.2063 mol) was added to a solution of (-3-yl) oxy) ethyl acetate and Ib (21 g, 0.0687 mol) in glacial acetic acid (400 ml), and the mixture was heated at 100 ° C. for 6 hours. After the reaction was completed, the reaction mixture was filtered through a bed of celite using ethyl acetate, 10% methanol and concentrated in vacuo. It was washed with methanol to give pure 6-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, I (12 g, 76.28%). C ₇ H ₅ BrN ₂ O ₂ of LCMS calculated value = 229.03, obs = 230.2.

6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (intermediate II) Synthesis of

Step 1: Synthesis of (but-3-en-1-yloxy) (tert-butyl) dimethylsilane, IIa: dichloromethane of stirred buta-3-en-1-ol (10 g, 0.1386 mol) cooled to 0 ° C. (150 ml) solution, triethylamine (19.64 g, 0.1941 mol) was added and stirred for 5 minutes. Next, tert-butyldimethylsilyl chloride (25.08 g, 0.1664 mol) and DMAP (catalytic amount) in dichloromethane were slowly added to the reaction mixture and stirred at 25 ° C. for 4 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with MTBE. The combined organic layers were washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo at 40 ° C., (but-3-en-1-yloxy) (tert-butyl) dimethylsilane , IIa (24 g, 93%). The crude material was set aside without any purification for the next step based on NMR monitoring of the reaction.

Step 2: tert-butyldimethyl (2- (oxiran-2-yl) ethoxy) silane, synthesis of IIb: stirred and cooled to 0 ° C. (but-3-en-1-yloxy) (tert-butyl) dimethylsilane M-CPBA (63.49 g, 0.2575 mol) was added little by little to a solution of IIa (24 g, 0.1287 mol) in dichloromethane (480 ml), and the mixture was stirred at 25 ° C. for 7 hours. After the reaction was completed, the reaction mixture was filtered to remove inorganics. Then it was quenched with 10% sodium thiosulfate and extracted with dichloromethane. The separated organic layer was washed with 10% sodium bicarbonate, brine solution, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo at 40 ° C. to give tert-butyldimethyl (2- (oxiran-2 There was obtained -yl) ethoxy) silane, IIb (22 g, 85%). The crude material was saved without any purification for the next step.

Step 3: 1-amino-4-((tert-butyldimethylsilyl) oxy) butan-2-ol, synthesis of IIc: stirred tert-butyldimethyl (2- (oxiran-2-yl) ethoxy) silane, IIb To a solution of (22 g, 0.1087 mol) in methanol (100 ml) was added NH ₃ in methanol (250 ml) and aqueous ammonia (100 ml) and stirred at 25 ° C. for 14 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give 1-amino-4-((tert-butyldimethylsilyl) oxy) butan-2-ol, IIc (20 g, 84%). The crude material was saved without any purification for the next step. C ₁₀ H ₂₅ NO ₂ Si of LCMS calculated value = 219.4, obs = 220.2.

Step 4: Synthesis of 5- (2-((tert-butyldimethylsilyl) oxy) ethyl) oxazolidin-2-one, IId: Stirred 1-amino-4-((tert-butyldimethylsilyl) cooled to 0 ° C. ) Oxy) butan-2-ol and IIc (20 g, 0.0912 mol) in THF (300 ml) were added in small portions with CDI (22.5 g, 0.1368 mol) and heated at 50 ° C for 14 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. Purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 35-40% ethyl acetate in petroleum ether to give 5- (2-((tert-butyldimethylsilyl) oxy) ethyl) oxazolidine-2- ON, IId (10 g, 45%) was obtained. C ₁₁ H ₂₃ NO ₃ Si of LCMS calculated value = 245.39, obs = 246.4.

Step 5: 6- (5- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine Synthesis of -3 (4H) -one, IIe: stirred 6-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, I (0.3 g, 0.0013 mol) And 5- (2-((tert-butyldimethylsilyl) oxy) ethyl) oxazolidin-2-one, IId (0.385 g, 0.0015 mol) in dry THF (10 ml) from Aldrich, t-butyl-X- Phos mesyl chloride complex (0.051 g, 0.00006 mol) and sodium tert-butoxide (0.187 g, 0.0019 mol) were added and degassed for 20 minutes. Next, it was irradiated with microwaves at 100 ° C. for 25 minutes. After the reaction was completed, the reaction mixture was concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 21-25% ethyl acetate in petroleum ether to give 6- (5- (2-((tert-butyldimethylsilyl) oxy) Ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIe (0.2 g, 40%) was obtained. _{C 18 H 27 N 3 O 5} Si of LCMS calculated value = 393.52, obs = 394.5.

Step 6: 6- (5- (2-hydroxyethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIf Synthesis of: Stirred 6- (5- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b ] To a solution of [1,4] oxazin-3 (4H) -one, IIe (1 g, 0.0025 mol) in THF (15 ml), tert-butylammonium fluoride (1.99 g, 0.0076 mol) was added little by little, and the mixture was added at 25 ° C. For 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo, 6- (5- (2-hydroxyethyl) -2-oxo-oxazolidine-3-yl) A colorless gummy solid of -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIf (0.5 g, 71.63%) was obtained. The crude material was saved without any purification for the next step. C ₁₂ H ₁₃ N ₃ O ₅ of LCMS calculated value = 279.24, obs = 280.2.

Step 7: 2- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidin-5-yl) Synthesis of ethyl methanesulfonate, IIg: Stirred 6- (5- (2-hydroxyethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1, 4] To a dichloromethane solution of oxazin-3 (4H) -one, IIf (0.5 g, 0.0017 mol), triethylamine (0.543 g, 0.0053 mol) and mesyl chloride (0.155 g, 0.0013 mol) were added, and the mixture was added at 25 ° C. Stirred for hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with dichloromethane. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo, 2- (2-oxo-3- (3-oxo-3,4 Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidin-5-yl) ethyl methanesulfonate, a pale brown gummy solid of IIg (0.5 g, 82.50%) Was. The crude material was saved without any purification for the next step. _{C 13 H 15 N 3 O 7} LCMS calculated value of S = 357.34, obs = 358.4.

Step 8: 6- (5- (2-azidoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIh Synthesis: Stirred 2- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) cooled to 0 ° C. To a solution of oxazolidine-5-yl) ethyl methanesulfonate, IIg (0.5 g, 0.0013 mol) in DMF (10 ml) was added sodium azide (0.181 g, 0.0027 mol) and heated at 60 ° C. for 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 50-60% ethyl acetate in petroleum ether to give 6- (5- (2-azidoethyl) -2-oxooxazolidin-3- Il) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, a colorless solid of IIh (0.32 g, 81.01%). C ₁₂ H ₁₂ N ₆ O ₄ of LCMS calculated value = 304.27, obs = 305.5.

Step 9: 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (intermediate Synthesis of Form II): Stirred 6- (5- (2-azidoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) - one, 12 (0.32 g, 0.0010 mol) in THF: MeOH (1: 1) to (10ml) solution was added 10% palladium on carbon (30 mg), H ₂ bubble pressure (bladder pressure) 25 ℃ under For 3 hours. After the reaction was completed, the reaction mixture was filtered through a bed of celite using THF and MeOH, concentrated in vacuo to give 6- (5- (2-aminoethyl) -2-oxooxazolidine- A colorless solid of 3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, II (0.25 g, 89.92%) was obtained. The crude material was saved without any purification for the next step. ¹ H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 4.79-4.80 (m, 1H), 4.62 (s, 2H ), 4.21-4.25 (m, 1H), 3.73-3.77 (m, 1H), 2.87-2.90 (m, 2H), 1.75-1.88 (m, 2H), 1.36 (s, 2H); C ₁₂ H ₁₄ N LCMS calculated for ₄ O ₄ = 278.27 Observed = 279

6- (5- (3-aminopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (intermediate III) Synthesis of

  Step-1: 3- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidine-5-yl ) Synthesis of propanenitrile (IIIa): To a stirred solution of the starting material IIg (0.7 g, 1.96 mmol) in DMSO (5 mL) was added sodium cyanide (0.38 g, 7.84 mmol) and the resulting reaction mixture was added Heated at C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine solution (20 mL) and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography, eluting with 40% EtOAC in petroleum ether to give the title compound ( 0.1 g) was obtained as a cloudy white solid.

  Step-2: tert-butyl (3- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidine Synthesis of (-5-yl) propyl) carbamate (IIIb): In a stirred solution of the starting material, IIIa (0.1 g, 0.346 mmol) in methanol (5 mL), cobalt (II) chloride hexahydrate (0.41 g, 1.734 mmol) ) And Boc-anhydride (0.138 g, 0.692 mmol) were added at 0 ° C. After stirring for 5 minutes, sodium borohydride (40 mg, 1.038 mmol) was added and the reaction was warmed to room temperature and stirred for 4 hours. After complete consumption of the starting material, the reaction mixture was filtered through a bed of celite and the filtrate was concentrated on a rotary evaporator. The residue obtained was diluted with water and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with a brine solution (15 mL) and concentrated to give a crude residue, which was purified by column chromatography using 35% EtOAC in petroleum ether to give the title compound (50 mg) Was obtained as a pale yellow solid.

Step-3: 6- (5- (3-aminopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ( Synthesis of III). To a stirred solution of the starting material, IIIb (50 mg) in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added at 0 ° C. and stirred at RT for 3 h. After the reaction was completed, the reaction mixture was concentrated in vacuo and washed with petroleum ether to give the title compound (40 mg) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.71 (bs, 1H), δ 7.59 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 4.68-4.75 (m, 1H), 4.61 (s, 2H), 4.22 (dd, J = 8.4, 10 Hz, 1H), 3.70 (dd, J = 6.6 Hz, 10 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H) , 1.73-1.81 (m, 2H), 1.61-1.71 (m, 2H); C 13 LCMS calculated value of H ₁₆ N ₄ O ₄ = 292.30 obs = 293.2.

6- (5- (3-aminopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (intermediate III) Alternative synthetic route

Step 1: Synthesis of (penta-3-en-1-yloxy) (tert-butyl) dimethylsilane, IIIc: A solution of penta-3-en-1-ol (20 g, 0.232 mol) in dichloromethane (200 ml) was added After cooling to 0 ° C. and adding triethylamine (45.01 mL, 0.325 mol), tert-butyldimethylsilyl chloride (50.3 g, 0.0.278 mol) and DMAP (0.56 g, 4.644 mmol) were added to the reaction mixture. For 4 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane (100 mL) and washed sequentially with water and brine solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo at 40 ° C. to give (penta-3-en-1-yloxy) (tert-butyl) dimethylsilane, IIIc (42.06 g). The crude material was saved without any purification for the next step. ¹ HNMR (DMSO-d6) δ 5.76-5.86 (m, 1H), 4.93-5.04 (m, 2H), 3.58 (t, J = 8.4 hz, 2H), 2.02-2.10 (m, 2H), 1.49-1.58 (m, 2H), 0.93 (s, 9H), 0.09 (s, 6H)

Step 2: tert-butyldimethyl (2- (oxiran-2-yl) ethoxy) silane, synthesis of IIId: stirred (penta-3-en-1-yloxy) (tert-butyl) dimethylsilane, IIIc (25 g, 0.125 mol) in dichloromethane (500 ml) was cooled to 0 ° C. and m-CPBA (63.49 g, 0.2575 mol) was added in portions over 20 minutes. After the addition was complete, the reaction was warmed to 25 ° C. and stirred for 7 hours. The reaction mixture was filtered to remove inorganics. Then it was quenched with 10% sodium thiosulfate and extracted with dichloromethane. The separated organic layer was washed with 10% sodium bicarbonate, brine solution, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo at 40 ° C. to give tert-butyldimethyl (2- (oxiran-2 -Yl) ethoxy) silane, IIId (21 g) was obtained. The crude material was saved without any purification for the next step.

Step 3: Synthesis of Intermediate IIIe: To a mixture of epoxide IIId (9 g, 0.039 mol) and ethyl carbamate (3.5 g, 0.039 mol) in a sealed tube was added triethylamine (5 mL, 0.039 mol) and the mixture was 145 Heated at 0 C overnight. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to give Intermediate IIIe (4.0 g). LCMS calculated for C ₁₂ H ₂₅ NO ₃ Si 259.42, observed = 260.0

Step 4: 6- (5- (2-((tert-butyldimethylsilyl) oxy) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine -3 (4H) -one, IIIf: stirred 6-bromo-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, I (0.300 g, 1.310 mmol) and 5 To a solution of-(2-((tert-butyldimethylsilyl) oxy) propyl) oxazolidin-2-one, IIIe (0.407 g, 1.572 mmol) in dry THF (12 ml) from Aldrich, was added t-butyl-X-Phos mesyl. Chloride complex (0.052 g, 0.0655 mmol) and sodium tert-butoxide (0.189 g, 1.965 mmol) were added and degassed for 20 minutes. Next, it was irradiated with microwaves at 100 ° C. for 40 minutes. After the reaction was completed, the reaction mixture was concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 21-25% ethyl acetate in petroleum ether to give 6- (5- (2-((tert-butyldimethylsilyl) oxy) Propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIIf (0.231 g) was obtained. _{C 19 H 29 N 3 O 5} Si of LCMS calculated value 407.42 obs = 408

Step 5: 6- (5- (3-hydroxypropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIIg Synthesis of 6- (5- (2-((tert-butyldimethylsilyl) oxy) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b To a solution of [1,4] oxazin-3 (4H) -one, IIIf (4.3 g, 0.0105 mol) in THF (45 ml), tert-butylammonium fluoride (5.64 g, 0.0216 mol) was added little by little, and 25 Stirred at C for 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo, 6- (5- (3-hydroxypropyl) -2-oxo-oxazolidine-3-yl) A colorless gummy solid of -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIIg (2.95 g, 95.81%) was obtained. The crude material was saved without any purification for the next step. LCMS calculated value of _{C 13 H 15 N 3 O 5} = 293.28, obs = 293.8.

Step 6: 3- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidin-5-yl) Synthesis of propylmethanesulfonate, IIIh: stirred 6- (5- (3-hydroxypropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1, 4] To a solution of oxazin-3 (4H) -one, IIIg (2.95 g, 0.010 mol) in dichloromethane (30 ml), triethylamine (3.05 g, 0.030 mol) and mesyl chloride (1.14 g, 0.010 mol) were added, and 25 Stirred at C for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with dichloromethane. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo to 3- (2-oxo-3- (3-oxo-3,4 Dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) oxazolidine-5-yl) propylmethanesulfonate, IIIh (2.8 g, 75.47%), a pale brown gummy solid. Was. The crude material was saved without any purification for the next step. _{C 14 H 17 N 3 O 7} LCMS calculated value of S = 371.36, obs = 371.8.

Step 7: 6- (5- (3-azidopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, IIIi Synthesis of 3- (2-oxo-3- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) stirred at 0 ° C. ) Oxazolidin-5-yl) propylmethanesulfonate, IIIh (2.8 g, 0.0075 mol) in DMF (30 ml) was added with sodium azide (0.98 g, 0.0150 mol) and heated at 60 ° C for 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 38-43% ethyl acetate in petroleum ether to give 6- (5- (3-azidopropyl) -2-oxooxazolidin-3. -Yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, a colorless solid of IIIi (1.5 g, 63.02%). C ₁₃ H ₁₄ N ₆ O ₄ of LCMS calculated value = 318.29, obs = 318.8.

Step 8: 6- (5- (3-aminopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, III Synthesis of: stirred 6- (5- (3-azidopropyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one To a solution of IIIi (1.3 g, 0.0010 mol) in THF: MeOH (1: 1) (10 ml) was added 10% palladium on carbon (0.6 g) and stirred at 25 ° C. under H ₂ bubble pressure for 3 h. . After the reaction was completed, the reaction mixture was filtered through a bed of celite using THF and MeOH and concentrated in vacuo to give 6- (5- (3-aminopropyl) -2-oxooxazolidine- A colorless solid of 3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, III (0.8 g, 67.22%) was obtained. The crude material was saved without any purification for the next step. ¹ H NMR (400 MHz, DMSO-d6) δ 7.71 (bs, 1H), δ 7.59 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 4.68-4.75 (m, 1H), 4.61 (s, 2H), 4.22 (dd, J = 8.4, 10 Hz, 1H), 3.70 (dd, J = 6.6 Hz, 10 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H) , 1.73-1.81 (m, 2H), 1.61-1.71 (m, 2H); LCMS calculated for C ₁₃ H ₁₆ N ₄ O ₄ = 292.30 Observed = 293.2.s

Synthesis of 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-benzo [b] [1,4] oxazin-3 (4H) -one (intermediate IV)

  Intermediate IV, 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-benzo [b] [1,4] oxazin-3 (4H) -one (CAS number 1072793- 84-0) was synthesized as already recorded in WO 2008126024.

Synthesis of 5- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile (intermediate V)

Step 1: Synthesis of 5-((4-((tert-butyldimethylsilyl) oxy) -2-hydroxybutyl) amino) -2-methylnicotinonitrile, Va: Stirred 5-bromo-2-methylnicotino To a solution of nitrile (850 mg, 4.31 mmol) and 5- (2-((tert-butyldimethylsilyl) oxy) ethyl) oxazolidin-2-one, IId (1268 mg, 5.17 mmol) in dry Aldrich THF (25 ml), t-Butyl-X-Phos mesyl chloride complex (171 mg, 0.21 mmol) and sodium tert-butoxide (621 mg, 6.47 mmol) were added and degassed for 20 minutes. Next, it was irradiated with microwaves at 100 ° C. for 20 minutes. After the reaction was completed, the reaction mixture was concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 26-30% ethyl acetate in petroleum ether to give 5-((4-((tert-butyldimethylsilyl) oxy) -2. -Hydroxybutyl) amino) -2-methylnicotinonitrile, Va (500 mg, 35%) was obtained. _{C 17 H 29 N 3 O 2} Si of LCMS calculated value = 335.52, obs = 336.2.

Step 2: Synthesis of 5- (5- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, Vb: cooled to 0 ° C. Stirred 5-((4-((tert-butyldimethylsilyl) oxy) -2-hydroxybutyl) amino) -2-methylnicotinonitrile, Va (500 mg, 1.49 mmol) in dry dichloromethane (Dichlormethane) (5 ml) To the solution was added triethylamine (754 mg, 7.54 mmol) and phosgene (1170 mg, 11.92 mmol) and stirred at 25 ° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 25-27% ethyl acetate in petroleum ether to give 5- (5- (2-((tert-butyldimethylsilyl) oxy) Ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, Vb (340 mg, 64%) was obtained. _{C 18 H 27 N 3 O 3} Si of LCMS calculated value = 361.52, obs = 362.

Step 3: Synthesis of 5- (5- (2-hydroxyethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, Vc: Stirring cooled to 0 ° C and stirring 5- (5- (2 -((tert-butyldimethylsilyl) oxy) ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, a solution of Vb (340 mg, 0.94 mmol) in THF (8 ml), tert-butyl fluoride Ammonium (737 mg, 2.82 mmol) was added in portions and stirred at 25 ° C. for 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo, 5- (5- (2-hydroxyethyl) -2-oxo-oxazolidine-3-yl) A colorless gummy solid of 2-methylnicotinonitrile, Vc (200 mg, 86.2%) was obtained. The crude material was saved without any purification for the next step. C ₁₂ H ₁₃ N ₃ O ₃ of LCMS calculated value = 247.25, obs = 247.8.

Step 4: Synthesis of 2- (3- (5-cyano-6-methylpyridin-3-yl) -2-oxooxazolidin-5-yl) ethylmethanesulfonate, Vd: cooled to 0 ° C. and stirred 5- ( 5- (2-hydroxyethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, a solution of Vc (200 mg, 0.80 mmol) in dichloromethane, triethylamine (245 mg, 2.42 mmol) and mesyl chloride (91 mg , 0.80 mmol) and stirred at 25 ° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with dichloromethane. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo to give 2- (3- (5-cyano-6-methylpyridin-3-yl ) -2-Oxooxazolidin-5-yl) ethyl methanesulfonate, a light brown gummy solid of Vd (200 mg, 77%). The crude material was saved without any purification for the next step. _{C 13 H 15 N 3 O 5} LCMS calculated value of S = 325.34, obs = 326.

Step 5: Synthesis of 5- (5- (2-azidoethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, Ve: cooled to 0 ° C. and stirred 2- (3- (5- To a solution of cyano-6-methylpyridin-3-yl) -2-oxooxazolidin-5-yl) ethyl methanesulfonate, Vd (200 mg, 0.614 mmol) in DMF (4 ml), sodium azide (59 mg, 0.92 mmol) was added. And heated at 60 ° C. for 3 hours. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography (230-400 mesh) with a gradient elution of 48-52% ethyl acetate in petroleum ether to give 5- (5- (2-azidoethyl) -2-oxooxazolidin-3- A colorless gummy solid of yl) -2-methylnicotinonitrile, Ve (100 mg, 60%) was obtained. C ₁₂ H ₁₂ N ₆ O ₂ of LCMS calculated value = 272.27, obs = 273.5.

Step 6: Synthesis of 5- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2-methylnicotinonitrile, V: Stirred 5- (5- (2-azidoethyl) -2 To a solution of -oxooxazolidin-3-yl) -2-methylnicotinonitrile, Ve (50 mg, 0.183 mmol) in methanol (5 ml) was added triethylamine (74 mg, 0.734 mmol) and 1,3-propanedithiol (79 mg, 0.734 mmol). ) Was added and stirred at 25 ° C. for 12 hours. After completion of the reaction, the reaction mixture was filtered to remove inorganics and concentrated in vacuo to give 5- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2-methyl A pale green crude of a gummy liquid of nicotinonitrile, V (43 mg, 95%) was obtained. The crude material was saved without any purification for the next step. C ₁₂ H ₁₄ N ₄ O ₂ of LCMS calculated value = 246.27, obs = 247.0.

Synthesis of 1-methyl-2-oxoindoline-7-carbaldehyde, intermediate VI

  Step-1: Synthesis of VIa: A solution of chloral hydrate (5.28 g, 31.9 mmol) in deionized water (90 mL), sodium sulfate (53.6 g, 377.9 mmol), 2-bromoaniline (5 g, 29.11 mmol), After addition of sulfuric acid (20 mL), hydroxylamine hydrochloride (6.66 g, 87.2 mmol) was added and the whole mixture was heated at 130 ° C. for 30 minutes. The mixture was cooled to room temperature, poured onto an ice-water mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude was saved without any purification for the next step.

  Step-2: Sulfuric acid (50 mL) was added to the crude obtained in step 1, and the mixture was heated at 70 ° C for 1 hour. After complete consumption of the starting material, the reaction mixture was poured on ice and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by silica gel column chromatography by using 20% ethyl acetate in petroleum ether for elution to give 2.5 g of VIa.

  Step-3: Synthesis of VIb: To a solution of VIa (2.5 g, 11.061 mmol) in ethanol (50 mL), hydrazine hydrate (99%, 0.5 mL) was added, and the mixture was refluxed under a nitrogen atmosphere for 30 minutes. . The yellow precipitate formed was isolated by filtration and suspended in absolute ethanol. Potassium tert-butoxide (4.03 g, 35.90 mmol) was added to the previous suspension. The mixture was refluxed for 2 hours. After the reaction was completed, the mixture was poured over ice water and acidified to pH 2 with dilute HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude VIb (0.89 g), which was taken up without any purification for the next step Oita.

  Step-4: Preparation of VIc: To a suspension of VIb (200 mg, 0.94 mmol) in water (5 mL) and sodium hydroxide (56 mg, 1.41 mmol), dimethyl sulfate (178 mg, 1.41 mmol) was added, and the mixture was added to 100 Heated at C for 1 hour. After consumption of the starting material, the reaction mixture was cooled to 0 ° C., water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude thus obtained was purified by column chromatography using 10% ethyl acetate in petroleum ether to give pure VIc (180 mg).

  Step-5: Preparation of VId: To a solution of VIc (180 mg, 0.79 mmol) in DMF (4 mL), after adding tributylvinyltin (0.26 mL, 2.25 mmol), palladium tetrakis-triphenylphosphine (45 mg, 0.103 mmol) Was added and the mixture was degassed for 30 minutes by purging with argon. The reaction was heated at 100 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to 0 ° C, water was added, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Therefore, the resulting crude was purified by column chromatography by using 10% ethyl acetate in petroleum ether to give pure VId (100 mg).

Step-6: Preparation of VI: The olefin VId (100 mg, 0.52 mmol) was dissolved in 4 mL of methanol and purged with oxygen for 10 minutes. The mixture was then cooled to -78 C and ozone was passed continuously through the reaction mixture for 30 minutes. After complete consumption of the VId, the reaction mass was quenched with dimethyl sulfide (0.5 mL) and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography with an eluent of 15% ethyl acetate in petroleum ether to give a pale yellow solid (30mg). ¹ HNMR (400MHz, CDCl ₃ ) δ 10.45 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 1.2, 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 3.60 (s, 2H), 3.55 (s, 3H); UPLCMS calculated for C ₁₀ H ₉ NO ₂ = 175.19, Observed = 175.8

Synthesis of 1-methyl-2-oxoindoline-7-carbaldehyde, intermediate VII

  Step-1: Synthesis of VIIa: A solution of chloral hydrate (9.55 g, 57.89 mmol) in deionized water (150 mL), sodium sulfate (100 g, 684.19 mmol), 3-bromo-2-fluoroaniline (10 g, 52.63 mmol) ), Sulfuric acid (40 mL) was added followed by hydroxylamine hydrochloride (10.97 g, 157.89 mmol) and the whole mixture was heated at 130 ° C. for 30 minutes. The mixture was cooled to room temperature, poured into an ice-water mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude was saved without any purification for the next step.

  Step-2: Sulfuric acid (100 mL) was added to the crude obtained in step 1, and the mixture was heated at 70 ° C for 1 hour. After complete consumption of the starting material, the reaction mixture was poured on ice and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by silica gel column chromatography by using 20% ethyl acetate in petroleum ether for elution to give 7.5 g of VIIa.

  Step-3: Preparation of VIIb: To a solution of VIIa (2.8 g, 11.48 mmol) in ethanol (50 mL), hydrazine hydrate (99%, 0.5 mL) was added, and the mixture was refluxed for 30 minutes under a nitrogen atmosphere. . The yellow precipitate formed was isolated by filtration and suspended in absolute ethanol. Potassium tert-butoxide (4.03 g, 35.90 mmol) was added to the previous suspension. The mixture was refluxed for 2 hours. After the reaction was completed, the mixture was poured over ice water and acidified to pH 2 with dilute HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude VIIb (2.0 g), which was taken without any purification for the next step Oita.

  Step-4: Preparation of VIIc: To a suspension of VIIb (1 g, 4.34 mmol) in water (30 mL) and sodium hydroxide (0.397 g, 13.04 mmol), add dimethyl sulfate (1.4 mL, 13.04 mmol) and mix Was heated at 100 ° C. for 2 hours. After consumption of the starting material, the reaction mixture was cooled to 0 ° C., water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Thus, the resulting crude was purified by column chromatography by using 21% ethyl acetate in petroleum ether to give pure VIIc (0.500 g).

  Step-5: Preparation of VIId: To a solution of VIIc (0.500 g, 2.04 mmol) in DMF (10 mL) was added tributylvinyltin (0.65 mL, 2.25 mmol) followed by palladium tetrakis-triphenylphosphine (0.118 g, 0.103 g). mmol) was added and the mixture was degassed for 30 minutes by purging with argon. The reaction was heated at 100 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to 0 ° C, water was added, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Thus, the resulting crude was purified by column chromatography by using 40% dichloromethane in petroleum ether to give pure VIId (0.300 g).

Step-6: Preparation of VII: Olefin VIId (0.300 g, 1.57 mmol) was dissolved in 10 mL of methanol purged with oxygen for 10 minutes. Next, the mixture was cooled to -40 ° C and ozone was continuously passed through the reaction mixture for 30 minutes. After complete consumption of VIId, the reaction mass was quenched with dimethyl sulfide (0.5 mL) and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography with an eluent of 40% ethyl acetate in petroleum ether to give a fluffy white solid (0.050 g). ¹ HNMR (400MHz, CDCl ₃ ) δ 10.47 (s, 1H), 7.34-7.37 (m, 1H), 6.78-6.83 (m, 1H), 3.53 (s, 2H), 3.35 (s, 3H); C ₁₀ UPLCMS calculated for H ₈ FNO ₂ = 193.18, Observed = 194.1

Synthesis of 6-fluoro-1,3,3-trimethyl-2-oxoindoline-7-carbaldehyde, intermediate VIII

  Step-1: Preparation of VIIIa: To a solution of VIIb (0.200 g, 0.869 mmol) in DMF (5 mL) was added sodium hydride (60%, 0.140 g, 3.478 mmol) at 0 ° C. After stirring at the same temperature for 5 minutes, methyl iodide (2 mL, 3.478 mmol) was slowly introduced, the reaction temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. After the reaction was completed, the whole reaction mixture was slowly poured onto ice-cold water and extracted with ethyl acetate. The crude obtained after evaporation of the solvent was purified by column chromatography by using 10% ethyl acetate in hexane to give 0.180 g of VIIIa.

  Step-2: Preparation of VIIIb: To a solution of VIIIa (0.180 g, 0.66 mmol) in DMF (5 mL) was added tributylvinyltin (0.2 mL, 0.727 mmol), and then palladium tetrakis-triphenylphosphine (0.038 g, 0.033 g). mmol) was added and the mixture was degassed for 30 minutes by purging with argon. The reaction was heated at 100 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to 0 ° C, water was added, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Thus, the resulting crude was purified by column chromatography by using 40% dichloromethane in petroleum ether to give pure VIIIb (0.080 g).

Step-3: Preparation of VIII: Olefin VIIIb (0.080 g, 3.65 mmol) was dissolved in 5 mL of methanol purged with oxygen for 10 minutes. Next, the mixture was cooled to -40 ° C and ozone was continuously passed through the reaction mixture for 30 minutes. After complete consumption of VIIIb, the reaction mass was quenched with dimethyl sulfide (0.5 mL) and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography with an eluent of 40% ethyl acetate in petroleum ether to give a fluffy white solid (0.038g). The structure was confirmed by NMR. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.48 (s, 1H), 7.27-7.32 (m, 1H), 6.79-6.84 (m, 1H), 3.36 (s, 3H), 1.38 (s, 6H).

Synthesis of 1-ethyl-6-fluoro-2-oxoindoline-7-carbaldehyde, intermediate IX

Step -1: IXa Preparation of: isatin intermediates VIIa (6.6g, 27.04mmol) in DMF (66 mL) solution _{of, K 2 CO 3 (5.4g,} 39.08mmol) and ethyl iodide (5.8mL, 72.51mmol) It was added continuously at room temperature under a nitrogen atmosphere. After stirring at rt for 2 hours, the reaction mixture was cooled in an ice bath and water (100 mL) was added. The whole mixture was extracted with ethyl acetate. The organic layer was washed with cold water, then sequentially with brine, dried over sodium sulfate and evaporated on a rotary evaporator. The obtained crude residue was suspended in n-hexane and stirred for 20 minutes. The solid was isolated by filtration to yield intermediate IXa (4.63 g).

Step-2: Preparation of IXb: Hydrazine hydrate (0.5 mL) was added to a solution of intermediate IXa (0.300 g) in ethanol and the mixture was heated to 130 ° C in a sealed tube. After 2 hours, a normal aqueous workup was performed to isolate the crude solid, which was purified by column chromatography using an eluent of 30% ethyl acetate in petroleum ether. This gave 140 mg of the compound IXb. UPLC calculated value of C ₁₀ H ₉ BrFNO; 258.09, obs = 258.0.

Step-3: Preparation of IXc: To a solution of IXb (1.0 g, 3.815 mmol) in DMF (20 mL) was added tributylvinyltin (1.3 mL, 4.263 mmol), and then palladium tetrakis-triphenylphosphine (0.223 g, 0.193 mmol) was added and the mixture was degassed for 30 minutes by purging with argon. The reaction was heated at 100 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to 0 ° C, water was added, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. Thus, the resulting crude was purified by column chromatography by using 40% dichloromethane in petroleum ether to give pure IXc (0.370 g). C ₁₂ H ₁₂ FNO of LCMS calculated value 205.09 obs = 205.8

Step-4: Preparation of IX: Olefin IXc (0.300 g, 1.57 mmol) was dissolved in 10 mL of methanol purged with oxygen for 10 minutes. Next, the mixture was cooled to -40 ° C and ozone was continuously passed through the reaction mixture for 30 minutes. After complete consumption, the reaction mass was quenched with dimethyl sulfide (0.5 mL) and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography with an eluent of 40% ethyl acetate in petroleum ether to give a fluffy white solid of aldehyde IX (0.090 g). ¹ HNMR (400MHz, CDCl ₃ ) δ 10.46 (s, 1H), 7.34-7.37 (m, 1H), 6.78-6.83 (m, 1H), 4.13, 4.10 (ABq, J = 7.0 Hz, 2H), 3.52 ( s, 2H), 1.12 (t, J = 7.0 Hz, 1H); Calculated UPLCMS for C ₁₁ H ₁₀ FNO ₂ = 207.20, Observed = 208

Synthesis of 2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) acetaldehyde, intermediate X

Step 1: Synthesis of 7-allyl-6-fluoro-1-methylindoline-2-one (Xa)
To a solution of VIIc (0.5 g, 2.049 mmol) in DMF (8 mL) was added allyltributyltin (tributylltin) (0.45 mL, 1.45 mmol), and then tetrakis (triphenylphosphine) palladium (0) (0.15 g, 0.13 mmol). Was added and the mixture was degassed for 30 minutes by purging with argon. The reaction was heated at 100 ° C. for 4 hours. After the reaction was completed, the mixture was cooled to 0 ° C., diluted with water, and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by silica gel column chromatography (230-400 mesh, 15% EtOAc in petroleum ether) to give pure Xa (0.255 g). C ₁₂ H ₁₂ UPLC_MS calculated value FNO, 205.23; observed value 206.5 [M ^{+ +} H].

Step 2: Synthesis of 2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) acetaldehyde (X) Intermediate Xa (0.15 g, 0.731 mmol) was dissolved in 5 mL of DCM, and heated to -78 ° C. Cool. Ozone was passed continuously through the reaction mixture for 30 minutes. After complete consumption of Xa, the reaction mass was quenched with dimethyl sulfide (0.2 mL) and evaporated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (230-400 mesh, 10% ethyl acetate in petroleum ether) to give X (0.125 g). This, GCMS calculated value of _{C 11 H 10 FNO 2, 207.20} ; characterized by observations 207.0 [M ^+].

  Intermediate XI, 6- (5- (3-aminopropyl) -2-oxooxazolidin-3-yl) -2H-benzo [b] [1,4] oxazin-3 (4H) -one (CAS number 1072800- 19-1) was synthesized as already recorded in WO 2008126024.

Synthesis of 2- (5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-4-yl) acetaldehyde (XII)

Step 1: Synthesis of 3-bromo-4-fluoro-2-nitrophenol (XIIa)
To a suspension of 3-bromo-4-fluorophenol (8.00 g, 42.0 mmol) and nickel (II) ammonium sulfate hexahydrate (8.00 g, 20.5 mmol) in 100 mL of dichloromethane was added 6 mL of nitric acid over 10 minutes. The internal temperature was kept below 25 ° C. with an ice bath. The resulting mixture was stirred for 20 minutes and poured into 250 g of crushed ice. The layers were separated, and the aqueous phase was extracted with dichloromethane (2 × 100 mL). The organic layers were combined, washed with brine solution (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (60-120 mesh), eluting with 70% dichloromethane in hexane to give product XIIa as a yellow solid. Yield: (3.00 g, 31%); ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H;); UPLC-MS: Observed for C ₆ H ₃ BrFNO ₃ = 234.93; Observed 235.9 [M + H] ⁺ .

Step 2: Synthesis of 2-amino-3-bromo-4-fluorophenol (XIIb) To a stirred solution of XIIa (3.00 g, 12.7 mmol) in methanol (50 mL) was added NiCl ₂ (3.20 g, 25.4 mmol) and NaBH ₄ (1.44 g, 38.0 mmol) was added and stirred at room temperature for 10 minutes. The reaction mixture was filtered and washed with ethyl acetate (200mL). The filtrate was concentrated to give crude XIIb (2.0 grams). The crude product was used without any further purification for the next step.

Step 3: Synthesis of 4-bromo-5-fluorobenzo [d] oxazol-2 (3H) -one (XIIc) To a stirred solution of XIIb (2.00 g, 9.70 mmol) in THF (30 mL) was added CDI (2.04 g, 12.6 mmol) was added and heated at 70 ° C. for 12 hours. After completion, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na ₂ SO _4, and concentrated in vacuo to give the crude product. The crude was purified by column chromatography using silica gel (60-120 mesh), eluting with 25% EtOAc in hexane to give the product XIIc (2.00 g, 67%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.02 (brs, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H) .C ₇ H ₃ BrFNO LC_MS Calculated for ₂ = 230.93; Observed 232.0 [M + H] ⁺ .

Step 4: Synthesis of 4-bromo-5-fluoro-3-methylbenzo [d] oxazol-2 (3H) -one (XIId) To a stirred solution of XIIc (1.50 g, 6.50 mmol) in acetonitrile (20 mL) was added K ₂ CO ₃ (2.69 g, 19.5 mmol) and Me ₂ SO ₄ (1.70 mL, 19.5 mmol) were added and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50mL) and washed with water (2x30mL). The organic layer was dried over Na ₂ SO _4, and concentrated in vacuo to give the crude product, thereby the column chromatography using silica gel (60-120 mesh) eluting with 25% ethyl acetate in hexane To give the product XIId (1.00 g, 62%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.40 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.40 (s, 1H).

Step 5: Synthesis of 4-allyl-5-fluoro-3-methylbenzo [d] oxazol-2 (3H) -one (XIIe)
To a solution of XIId (1.00 g, 4.06 mmol) in DMF (20 mL) was added tributylallyl tin (1.5 mL, 4.87 mmol) and the mixture was degassed for 30 minutes by purging with nitrogen before Pd (PPh ₃ ) ₄ (0.23 g, 0.20 mmol) was added. The reaction mixture was heated at 100 C for 8 hours. After completion, the reaction mixture was cooled to 0 ° C., quenched with water, and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na ₂ SO _4, evaporated under reduced pressure to give the crude product which, by column chromatography, silica gel (60 Purification by eluting with 20% ethyl acetate in petroleum ether using 120120 mesh) provided the pure product XIIe (0.45 grams, 53%).

Step 6: Synthesis of 2- (5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-4-yl) acetaldehyde (XII)
A solution of XIIe (0.30 g, 1.44 mmol) in methanol (10 mL) was purged with O ₃ at −78 ° C. for 10 minutes. The reaction mixture was quenched with dimethyl sulfide (1 mL) and stirred for 30 minutes. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (2 × 25 mL), washed with water (20 mL), brine solution (20 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give a crude The product XII (0.13 g, crude) was obtained. The crude was used without any further purification for the next step.

Synthesis of 7- (aminomethyl) -6-fluoro-1-methyl-1,3-dihydro-2H-pyrrolo [3,2-b] pyridin-2-one (XIII)

Step 1: Synthesis of 6-fluoro-1-methyl-1H-pyrrolo [3,2-b] pyridine (XIIIa)
To a solution of 6-fluoro-1H-pyrrolo [3,2-b] pyridine (CAS: 1190320-33-2, 6.5 g, 47.74 mmol) in dry DMF (65 mL) was added NaH (3.82 g, 95.49 mmol) at 0 ° C. Was added in several portions and then the reaction mixture was stirred at room temperature for 1 hour. Methyl iodide (5.30 mL, 95.49 mmol) was added at 0 ° C. and then stirred at room temperature for 2 hours. After consumption of the starting material, the reaction mixture was cooled to 0 ° C., water was added and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The crude was purified by column chromatography (230/400 mesh, 30% ethyl acetate in petroleum ether) to give the desired compound XIIIa as a white solid (6 g, 85%). LC_MS calculated for C8H7FN2 = 150.16; Acquired value: 151.1 ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 8.33 (s, 1H), 7.89-7.86 (m, 1H), 7.64 (d, 1H, J = 2.8 Hz), 6.58 (s, 1H), 3.80 (s, 3H).

Step 2: Synthesis of 6-fluoro-1-methyl-1H-pyrrolo [3,2-b] pyridine 4-oxide (XIIIb)
To a solution of XIIIa (6 g, 39.95 mmol) in dry DCM (120 mL) was added mCPBA (13.80 g, 79.91 mmol) in several portions at 0 ° C., then the reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed, the reaction mixture was cooled to 0 ° C., 10% aqueous NaHCO ₃ (100 mL) was added and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The crude was washed with n-hexane (2 × 100 mL) and then dried to give the desired compound XIIIb as a white solid (4 g, 62%). LC_MS calculated for C ₈ H ₇ FN ₂ O = 166.16; Acquired value: 167.1; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 8.34-8.33 (m, 1H), 7.71-7.69 (m, 1H) , 7.58-7.53 (m, 1H), 6.65 (d, 1H, J = 3.2 Hz), 3.81 (s, 3H).

Step 3: Synthesis of 7-chloro-6-fluoro-1-methyl-1H-pyrrolo [3,2-b] pyridine (XIIIc)
POCl ₃ (40 mL) was added in small portions to compound XIIIb (4 g, 24.07 mmol) at 0 ° C., then the reaction mixture was heated at 100 ° C. for 2 hours. After consumption of the starting material, the reaction mixture was cooled to 0 ° C., 10% aqueous NaHCO ₃ (100 mL) was added portionwise and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The crude was purified by column chromatography (230/400 mesh, 30% ethyl acetate in petroleum ether) to give the desired compound XIIIc as a white solid (2 g, 45%). LC_MS calculated for C ₈ H ₆ ClFN ₂ = 184.60; obtained: 185.2; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 8.43 (s, 1H), 7.71 (s, 1H), 6.63 (d, 1H, J = 3.6 Hz), 4.09 (s, 3H).

Step 4: Synthesis of 6-fluoro-1-methyl-1H-pyrrolo [3,2-b] pyridine-7-carbonitrile (XIIId)
To a solution of XIIIc (2 g, 10.83 mmol) in NMP (40 mL) was added zinc dust (14 mg, 0.21 mmol), Pd2dba3 (0.20 g, 0.21 mmol) and DPPF (0.24 g, 0.43 mmol) at 0 ° C., then The reaction mixture was purged with N ₂ for 15 minutes, then zinc cyanide (2.54 g, 21.66 mmol) was added and the reaction mixture was heated at 130 ° C. for 24 hours. After consumption of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The crude was purified by column chromatography (230/400 mesh, 30% ethyl acetate in petroleum ether) to give the desired compound XIIId as a white solid (1 g, 57%). LC_MS calculated for C ₉ H ₆ FN ₃ = 175.17; acquisition: 176.2; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 8.60 (s, 1H), 7.87-7.86 (m, 1H), 6.78- 6.76 (m, 1H), 4.05 (s, 3H).

Step 5: Synthesis of 3,3-dibromo-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridine-7-carbonitrile (XIIIe)
To a solution of XIIId (1 g, 5.70 mmol) in tert-butanol (30 mL) and water (30 mL), N-bromosuccinimide (2.03 g, 11.40 mmol) was added in several portions. Then the reaction mixture was stirred at room temperature for 1 hour. After consumption of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The resulting crude was washed with n-hexane to give pure compound XIIIe as a pale yellow solid (1 g, 57%). LC_MS calculated for C ₉ H ₄ Br ₂ FN ₃ O = 348.96; obtained: 349.7; ¹ H NMR (400 MHz, DMSO-D6): δ 8.49 (s, 1H), 3.52 (s, 3H).

Step 6: Synthesis of 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridine-7-carbonitrile (XIIIf)
To a solution of XIIIe (1 g, 2.86 mmol) in dry THF (10 mL) and saturated aqueous ammonium chloride solution (10 mL), zinc dust (3.74 g, 57.31 mmol) was added in several portions. Then the reaction mixture was stirred at room temperature for 16 hours. After consumption of the starting material, the reaction mixture was filtered through celite, diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The resulting crude was washed with n-hexane to give pure compound XIIIf as a pale yellow oil (0.5 g, 91%). LC_MS calculated for C ₉ H ₆ FN ₃ O = 191.17; Acquired value: 192.0; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 8.22 (s, 1H), 3.71 (s, 2H), 3.44 (s , 3H).

Step 7: Synthesis of tert-butyl ((6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridin-7-yl) methyl) carbamate (XIIIg)
To a solution of XIIIf (0.50 g, 2.61 mmol) in dry methanol (10 mL), add Boc anhydride (0.7 mL, 3.13 mmol) and nickel chloride (0.680 g, 5.23 mmol), then cool the reaction mixture to 0 ° C. Then, NaBH ₄ (0.297 g, 7.84 mmol) was added in several portions. Then the reaction mixture was stirred at room temperature for 30 minutes. After consumption of the starting material, the reaction mixture was filtered through celite, diluted with water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude. The crude was purified by column chromatography (230/400 mesh, 30% ethyl acetate in petroleum ether) to give the desired compound XIIIg as a white solid (0.35 g, 50%). LC_MS calculated for C ₁₄ H ₁₈ FN ₃ O ₃ = 295.31; acquisition: 296.2; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.06 (s, 2H), 8.08-8.06 (m, 1H), 7.45-7.40 (m, 1H), 4.38 (s, 2H), 3.65-3.64 (m, 2H), 2.56 (s, 9H).

Step 8: Synthesis of 7- (aminomethyl) -6-fluoro-1-methyl-1,3-dihydro-2H-pyrrolo [3,2-b] pyridin-2-one (XIII)
To a solution of XIIIf (0.35 g, 1.18 mmol) in dry DCM (7 mL) at 0 ° C. was added 4M HCl in 1,4-dioxane (2 mL), then the reaction mixture was stirred at room temperature for 1 hour. After consumption of the starting material, the reaction mixture was concentrated to dryness. The crude was dissolved in dry methanol (10 mL) neutralized by adding Amberlyst A26 resin at 0 ° C., filtered and evaporated under reduced pressure to give the crude. The crude obtained is washed with n-hexane to give XIII as a pale yellow oil (0.20 g, 90%), the product of which is set aside without further characterization.

(Example 1)
6- (5- (2-(((1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b ] [1,4] oxazine-3 (4H) -one

Stirred 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one II (45 mg , 0.161 mmol) and 1-methyl-2-oxoindoline-7-carbaldehyde VI (29 mg, 0.00018 mol) in dichloromethane: methanol (9: 1 = 5 ml). Stirred at C for 2 hours. After confirming the formation of the imine by ¹ H NMR, it was filtered and concentrated in vacuo. The residue obtained was dissolved in methanol, cooled to 0 ° C. and sodium borohydride (12 mg, 0.322 mmol) was added. The reaction was gradually warmed to 25 ° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. The residual mixture was extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by mass-based preparative purification to give the title compound (3 mg) as a white solid. ¹ H NMR (400 MHz, MeOD) δ 8.52 (bs, 1H), 7.70 (d, 8.8 Hz, 1H), 7.367 (dd, 1H, J = 8.8 Hz, 0.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 4.82 (m, 1H), 4.64 (s, 2H), 4.32 (t, J = 9.6 Hz, 1H), 3.89-3.93 (m, 1H ), 3.57 (s, 3H) , 3.03-3.09 (m, 1H), 2.18 (s, 2H), 2.01-2.08 (m, 2H). LCMS = C 22 H 23 N 5 O 5 calculated value = 437.56, Observed value = 438, HPLC = 89.04% (HPLC column: ATLANTIS dC18 (250 x 4.6) mm, 5μ, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile.

(Example 2)
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazine-3 (4H) -one

Stirred 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, II ( Glacial acetic acid (0.2 ml) was added to a solution of 0.26 g (0.0009 mol) and 6-fluoro-1-methyl-2-oxoindoline-7-carbaldehyde, VII (0.198 g, 0.0010 mol) in methanol (5 ml). And stirred at 25 ° C. for 2 hours. Next, the mixture was cooled to 0 ° C, sodium cyanoborohydride resin (0.0011 mol) was added, and the mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered to remove the resin, and the filtrate was concentrated in vacuo. It was purified by reverse phase preparative HPLC to give 6- (5- (2-(((5-fluoro-1-methyl-2-oxoindoline-4-yl) methyl) amino) ethyl) -2- A colorless solid was obtained (90 mg, 21.27%) which was a pure compound of oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one. ¹ H NMR (400 MHz, MeOD) δ = 7.71-7.73 (m, 1H), 7.38-7.42 (m, 2H), 6.95-7.00 (m, 1H), 4.82-4.89 (m, 1H), 4.64-4.67 ( m, 4H), 4.38-4.43 (m, 1H), 3.91-3.96 (m, 1H), 3.54 (s, 2H), 3.61 (s, 3H), 3.42-3.49 (m, 2H), 2.23-2.29 ( . m, 2H) LCMS calculated values of _{C 22 H 22 FN 5 O 5} = 455.16, observed value = 456.01, HPLC = 99.69% ( HPLC columns: ATLANTIS dC18 (250x4.6) mm, 5μ, mobile phase a: water 0.1 % TFA, mobile phase B: acetonitrile.

(Example 3)
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one

To a stirred solution of IV (40 mg, 0.144 mmol) and oxoindole VII (29 mg, 0.00018 mol) in dichloromethane: methanol (9: 1 = 5 ml) was added the molecular sieve (0.1 g) and the solution was added at 25 ° C. Stirred for hours. After confirming the formation of the imine by ¹ H NMR, it was filtered and concentrated in vacuo. The residue obtained was dissolved in methanol, cooled to 0 ° C. and sodium borohydride (12 mg, 0.322 mmol) was added. The reaction was gradually warmed to 25 ° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. The residual mixture was extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by mass-based preparative purification to give the title compound (3 mg) as a white solid. ¹ H NMR (400MHz, MeOD) 7.36-7.43 (m, 1H), 7.36-7.37 (m, 1H), 6.95-7.03 (m, 3H), 4.83-4.86 (m, 1H), 4.66 (s, 2H) , 4.57 (s, 2H), 4.24 (t, J = 8.8 Hz, 1H), 3.79-3.83 (m, 1H), 3.70 (s, 2H), 3.54 (s, 3H), 3.42-3.48 (m, 2H ), 2.26-2.31 (m, 2H) ; C 23 H 23 FN 4 O 5 of LCMS calculated value = 454.6 observations 455.

(Example 4)
6- (5- (2-(((6-fluoro-1,3,3-trimethyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H Of 1-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Stirred 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, II ( 0.045 g, 0.00016 mol) and 6-fluoro-1,3,3-trimethyl-2-oxoindoline-7-carbaldehyde, VIII (0.035 g, 0.00016 mol) in dichloromethane: methanol (9: 1 = 5 ml) solution. , A molecular sieve (0.1 g) was added, and the mixture was stirred at 25 ° C for 2 hours. After confirming the formation of the imine by ¹ H NMR, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in methanol, cooled to 0 ° C. and sodium borohydride (0.012 g, 0.00033 mol) was added. After the addition was complete, the reaction was gradually warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. It was extracted with ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. It was purified by silica gel column chromatography with a gradient elution of 4-5% methanol in dichloromethane to give 6- (5- (2-(((6-fluoro-1,3,3-trimethyl-2-oxo Indoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one white solid (21 mg, 21.27%). ¹ H NMR (400 MHz, MeOD) δ 7.58-7.69 (m, 1H), 7.35-7.37 (m, 1H), 7.21-7.24 (m, 1H), 4.79-4.80 (m, 1H), 4.633 (s, 2H ), 4.293-4.297 (m, 1H), 4.27 (s, 2H), 3.89-3.92 (m, 1H), 3.37 (s, 3H), 2.88-2.91 (m, 2H), 2.00-2.04 (m, 2H ), 1.30 (s 6H) .Calculated LCMS for C ₂₄ H ₂₆ FN ₅ O ₅ = 483.50, Observed = 484.5 HPLC = 92.99% (HPLC column: ATLANTIS dC18 (250x4.6) mm, 5μ, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile.

(Example 5)
5- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotino Synthesis of nitriles

Stirred 6- (5- (2-aminoethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, V ( 43 mg, 0.174 mmol) and a solution of 6-fluoro-1-methyl-2-oxoindoline-7-carbaldehyde (VII; 35 mg, 0.183 mmol) in dichloromethane: methanol (9: 1 = 5 ml) were charged with a molecular sieve (0.1 g). ) Was added and stirred at 25 ° C. for 2 hours. After confirming the formation of the imine by ¹ H NMR, it was filtered and concentrated in vacuo. It was dissolved in methanol, cooled to 0 ° C., added sodium borohydride (12 mg, 0.348 mmol) and stirred at 25 ° C. for 1.5 hours. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. It was extracted with ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. It was purified by reverse phase preparative HPLC to give 5- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-. Oxooxazolidin-3-yl) -2-methylnicotinonitrile, a colorless solid, a pure compound of BWC0136 (6 mg, 8%). Purification. ¹ H NMR (400 MHz, MeOD) δ = 8.89 (d, J = 2.8 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.25-7.29 (m, 1H), 6.84-6.88 (m, 1H ), 4.488-4.492 (m, 1H), 4.22-4.26 (m, 3H), 3.85-3.89 (m, 1H), 3.52-3.60 (m, 4H), 3.06-3.11 (m, 2H), 2.72 (s , 3H), 2.12-2.17 (m, 2H); calculation value of _{LCMS = C 22 H 22 FN 5} O 3 = 423.45, observed value = 424. HPLC = 94.92% (HPLC columns: ATLANTIS dC18 (250x4.6) mm , 5μ, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile).

(Example 6)
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazine-3 (4H) -one

To a stirred solution of the starting material, III (0.02 g, 0.068 mmol) in DCM / MeOH (9/1, 5 ml) was added the aldehyde, VII (13.15 mg, 0.068 mmol) followed by a molecular sieve (50 mg) and triethylamine (50 mg). A few drops) was added. The resulting reaction mixture was stirred at RT for 3 hours. After confirming the formation of the imine by ¹ H-NMR, the reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in methanol, cooled to 0 ° C. and sodium cyanoborohydride (5 mg, 0.136 mmol) was added. After stirring at RT for 2 hours, the reaction mixture was concentrated on a rotary evaporator. The residue obtained was diluted with water and extracted with ethyl acetate. The crude was purified by mass-based preparative purification to give the title compound (5 mg) as a pale yellow liquid. ¹ H NMR (400 MHz, MeOD) δ 8.44 (bs, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.30-7.34 (m, 1H), 6.87 -6.92 (m, 1H), 4.74-4.76 (m, 1H), 4.63 (s, 2H), 4.39 (s, 2H), 4.31-4.36 (m, 1H), 3.84-3.88 (m, 1H), 3.67 -3.70 (m, 2H), 3.54-3.58 9m, 5H), 3.08-3.10 (m, 2H), 1.84-1.90 (m, 4H); C 23 H 24 FN 5 O 5 of LCMS calculated value = 469.47 observations = 470.0; HPLC = 87.33% (Zorbax Eclipse plus C18 RRHD (50X2.1) mm, 1.8μ; mobile phase A: 0.1% TFA in water B: acetonitrile)

(Example 7)
6- (5- (2-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazine-3 (4H) -one

To a stirred solution of II (30 mg, 0.108 mmol) and oxoindole IX (23 mg, 0.113 mol) in dichloromethane: methanol (9: 1 = 5 ml) was added a molecular sieve (0.1 g), and the mixture was stirred at 25 ° C. for 2 hours. . After confirming the formation of the imine by ¹ H NMR, it was filtered and concentrated in vacuo. The residue obtained was dissolved in methanol, cooled to 0 ° C. and sodium borohydride (8 mg, 0.2162 mmol) was added. The reaction was gradually warmed to 25 ° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. The residual mixture was extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by mass-based preparative purification to give the title compound (7.2 mg) as a white solid. ¹ H NMR (400 MHz, MeOD) 8.35 (bs, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.33-7.30 (m, 1H), 6.92- 6.87 (m, 1H), 4.84-4.82 (m, 1H), 4.33 (t, J = 8.8 Hz, 1H), 4.23 (s, 2H), 4.02-4.08 (m, 2H), 3.89-3.93 (m, 1H), 3.53-3.70 (m, 2H), 3.13-3.16 (m, 2H), 2.68 (s, 1H), 2.12-2.14 (d, 2H), 1.27-1.31 (m, 2H); C ₂₄ H ₂₅ LCMS Calculated for FN ₄ O ₅ = 469.47 Observed 470.

(Example 8)
6- (5- (3-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazine-3 (4H) -one

To a stirred solution of III (20 mg, 0.0684 mmol) and oxoindole IX (15 mg, 0.0724 mol) in dichloromethane: methanol (9: 1 = 5 ml) was added a molecular sieve (0.1 g), and the mixture was stirred at 25 ° C. for 2 hours. . After confirming the formation of the imine by ¹ H NMR, it was filtered and concentrated in vacuo. The residue obtained was dissolved in methanol, cooled to 0 ° C. and sodium borohydride (8 mg, 0.2162 mmol) was added. The reaction was gradually warmed to 25 ° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was quenched with water and concentrated in vacuo to remove methanol. The residual mixture was extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over sodium sulfate and concentrated in vacuo. The crude was purified by mass-based preparative purification to give the title compound (3.3 mg) as a white solid. ^{1 H NMR (400MHz, MeOD)} 8.28 (bs, 1H), 7.71 (d, J = 8.8 Hz, 1H), 736-7.41 (m, 2H), 6.93-6.98 (m, 1H), 4.75-4.78 (m , 1H), 4.64 (s, 2H), 4.40 (s, 2H), 4.33-4.37 (m, 1H), 3.98-4.03 (m, 2H), 3.85-3.89 (m, 1H), 3.56-3.59 (m , 1H), 3.22 (t, J = 6.8 Hz, 2H); LCMS calculated for C ₂₅ H ₂₇ FN ₄ O ₅ = 483.5 Observed 484.

(Example 9)
Chiral 6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [ 3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1)

(Example 10)
Chiral 6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [ 3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2)

Glacial acetic acid (10 mL) was added to a stirred solution of III (4.95 g, 0.025 mol) in MeOH (370 mL), and then aldehyde, VII (4.825, 0.025 mol) was added, followed by stirring at 25 ° C. for 15 minutes. Next, after cooling the solution to 0 ° C, sodium cyanoborohydride resin (20 g, 0.050 mol) was added, and the mixture was stirred at 25 ° C for 6 hours. After the reaction was completed, the reaction mixture was filtered to remove the resin, and the filtrate was concentrated in vacuo. It was purified on silica gel by flash column chromatography (230-400 mesh, 8% MeOH in DCM) to give racemic Example 6 as a pale yellow solid (2.52 g, 21.48%). ¹ H NMR (400 MHz, CD ₃ OD) .δ 7.71 (d, J = 8.40 Hz, 1H), 7.37-7.43 (m, 2H), 7.0-6.94 (m, 1H), 4.87 (m, 1H), 4.79-4.7 (m, 1H), 4.7-4.6 (m, 4H), 4.34-4.39 (m, 1H), 3.9-3.8 (m, 1H), 3.61 (s, 2H), 3.52 (s, 3H), .. 1.91-1.97 (m, 4H) C 23 H 24 FN 5 O 5 of LC_MS calculated value = 469.47, observed value = 470.01 HPLC = 96.84% (HPLC columns: ATLANTIS dC18 (250x4.6) mm, 5μ, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile.

A portion of the racemate (Example 6, 2 grams) was separated into its enantiomers (Examples 9 and 10) by chiral supercritical fluid chromatography (SFC) using the following SCF conditions: .
Column: Lux C3 (250 x 30) mm
Mobile phase: CO ₂ : 20mm ammonia, in methanol (65:35)
Total flow rate: 100g / min Injection volume: 0.5ml
Back pressure: 100 barWavelength: 212 nm
Cycle time: 11.0 minutes

Two pure fractions were collected and their solvents were evaporated under vacuum to give enantiomers 1 and 2 as a cloudy white solid.
Enantiomer 1 (Example 9): 0.750 grams, chiral HPLC retention time: 5.74 minutes.
Enantiomer 2 (Example 10): 0.650 grams, chiral HPLC retention time: 7.38 minutes.

(Example 11)
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -one

Glacial acetic acid (0.2 mL) was added to a stirred solution of amine II (0.13 g, 0.467 mmol) and aldehyde X (0.125 g, 0.603 mmol) in MeOH (4 mL) and stirred at 25 ° C. for 15 minutes. Next, after cooling the solution to 0 ° C, sodium cyanoborohydride resin (0.125 g) was added, and the mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered to remove the resin, and the filtrate was concentrated in vacuo. It was purified by reverse-phase prep-HPLC to afford Example 11 as a pale yellow solid (21 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) .δ 11.22 (s, 1H), 8.77 (brs, 2H), 7.61 (d, 1H, J = 8.40 Hz), 7.45 (d, 1H J = 8.40 Hz) , 7.23-7.18 (m, 1H), 6.9-6.84 (m, 1H), 4.81-4.77 (m, 1H), 4.77 (s, 2H), 4.26 (t, 1H, J = 6 Hz), 3.60 (s , 2H), 3.42 (s, 3H), 3.23-3.15 (m, 6H), 2.15-2.10 (m, 2H) LC_MS calculated value of _{.C 23 H 24 FN 5 O 5} 469.47; observations 470.0.

(Example 12)
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one

To a stirred solution of XI (0.1 g, 0.34 mmol) and 6-fluoro-1-methyl-2-oxoindoline-7-carbaldehyde, VII (0.066 g, 0.34 mmol) in methanol (5 ml) was added glacial acetic acid (0.2 ml). ) Was added and stirred at 25 ° C. for 15 minutes. Next, the mixture was cooled to 0 ° C, sodium cyanoborohydride resin (0.295 g, 0.68 mmol) was added, and the mixture was stirred at 25 ° C for 6 hours. After the reaction was completed, the reaction mixture was filtered to remove the resin, and the filtrate was concentrated under reduced pressure. It was purified by reverse-phase prep-HPLC to give Example 12 (0.04 g, 25%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 8.79 (brs, 2H), 7.4-7.3 (m, 2H), 7.0-6.9 (m, 3H), 4.75-4.7 ( m, 1H), 4.55 (s, 2H), 4.5-4.4 (m, 2H), 3.7-3.63 (m, 3H), 3.41 (s, 3H), 3.2-3.16 (m, 2H), 1.85-1.7 ( _{m, 4H). C 24 H} 25 FN 4 O 5 of LC_MS calculated value = 468.49, observed value 469.0.

(Example 13)
Chiral 6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H- Pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1)

(Example 14)
Chiral 6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H- Pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2)

  AcOH (1 mL) was added to a mixture of X (1 g, 4.82 mmol) and amine II (1.60 g, 5.79 mmol) in dry MeOH (20 mL) and DCM (20 mL) and stirred for 16 hours. To this was added sodium cyanoborohydride resin (3.97 g, 9.65 mmol) and stirred for 15 minutes. The reaction mixture was filtered and concentrated. The crude was purified by column chromatography (230/400 mesh, 7% DCM in MeOH) to give a racemic mixture of compounds as a cloudy white solid (Example 11, 0.5 g, 26%).

A portion of the racemate (Example 11, 0.5 gram) was separated into its enantiomers (Example 13 and Example 14) by chiral supercritical fluid chromatography (SFC) using the following SCF conditions: .
Column: YMC cellulose Mobile phase: CO ₂ : 20 mm ammonia in methanol (65:35)
Flow rate: 4mL / min Injection volume: 0.5ml
Back pressure: 100 barWavelength: 212 nm
Cycle time: 11.0 minutes The pure fractions separated were collected and their solvents were evaporated under vacuum to give enantiomers 1 and 2 as cloudy white solids.
Enantiomer 1 (Example 13): 0.200 g, chiral HPLC retention time: 3.7 minutes
LC_MS calculated value of _{C 23 H 24 FN 5 O 5} , 469.47; observed value ^{470.0; [M + + H]} ; HPLC purity = 95.07% (HPLC column: Atlantis dC18 (250 × 4.6) mm 5μm, mobile phase A: water 0.1% TFA, mobile phase B: acetonitrile); ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.23 (s, 1H), 7.59 (d, 1H, J = 8.4 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.18-7.15 (m, 1H), 6.86-6.82 (m, 1H), 4.79-4.76 (m, 1H), 4.62 (s, 2H), 4.26-4.22 (m, 1H), 3.79 -3.75 (m, 1H), 3.53 (s, 2H), 3.12-3.10 (m, 2H), 2.96 (s, br, 4H), 2.03 (s, br, 2H).

Enantiomer 2 (Example 14): 0.200 g, chiral HPLC retention time: 4.5 minutes
LC_MS calculated value of _{C 23 H 24 FN 5 O 5} , 469.47; observed value ^{470.0; [M + + H]} ; HPLC purity = 97.02% (HPLC column: Atlantis dC18 (250 × 4.6) mm 5μm, mobile phase A: water 0.1% TFA, mobile phase B: acetonitrile); ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.20 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.13-7.09 (m, 1H), 6.82-6.78 (m, 1H), 4.76-4.73 (m, 1H), 4.61 (s, 2H), 4.23-4.18 (m, 1H), 3.76 -3.72 (m, 1H), 3.50 (s, 2H), 3.47 (s, 3H), 2.99-2.96 (m, 2H), 2.72-2.65 (m, 4H), 1.90-1.83 (m, 2H).

(Example 15)
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) -2-hydroxyethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Step 1: 6-fluoro-1-methyl-7- (oxiran-2-yl) indolin-2-one (15a)
To a solution of VIId (2 g, 10.45 mmol) in DCM (60 mL) and 5% aqueous NaHCO ₃ (20 mL) was added metachloroperbenzoic acid (5.41 g, 31.38 mmol) at 0 ° C. The reaction mass was stirred at room temperature for 16 hours. After the reaction was completed, 5% aqueous NaHCO ₃ (50 mL) was added and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude, giving compound 15a (1.3 g, 60% yield) as a cloudy white solid. LC_MS calculated for C ₁₁ H ₁₀ FNO ₂ = 207.20; observed 208.1 [M ⁺ + H] ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 7.90 (s, 1H), 7.72-7.52 (m, 1H ), 7.26-7.21 (m, 1H), 6.85-6.78 (m, 1H), 4.25 (s, 1H), 3.54 (s, 2H), 3.33 (s, 3H).

Step 2: 6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) -2-hydroxyethyl) amino) ethyl) -2-oxooxazolidin-3 -Yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one In ethanol (52 mL) and water (13 mL), 15a (1.3 g, 6.27 mmol) and amine II ( 2.09 g, 7.52 mmol) was heated in a sealed tube at 100 ° C. for 24 hours. After completion, the reaction mixture was concentrated to give the crude product. The crude was purified by reverse phase grace column chromatography to give the desired product (Example 15) as a cloudy white solid (0.3 g), only one of the diastereomers was ring-opened to epoxide 15a. Obtained from reaction. LC_MS calculated value of _{C 23 H 24 FN 5 O 6} , 485.47; observed value ^{486.2; [M + + H]} ; HPLC purity = 88.67% (HPLC column: Atlantis dC18 (250 × 4.6) mm 5μm, mobile phase A: water 0.1% TFA, mobile phase B: acetonitrile); ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.22 (s, 1H), 8.78 (s, 1H), 7.59 (d, 1H, J = 8.4 Hz) , 7.45 (d, 1H, J = 8.8 Hz), 7.25 (s, br, 1H), 6.31 (s, 1H), 4.79-4.78 (m, 1H), 4.62 (s, 1H), 4.28-4.23 (m , 2H), 3.61 (s, 3H), 3.46 (s, 3H), 3.17 (s, 2H), 2.16-2.09 (m, 2H).

(Example 16)
6- (5- (2-((2- (5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-4-yl) ethyl) amino) ethyl) -2-oxo Oxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

AcOH (0.10 mL) was added to a mixture of XII (0.12 g, 0.57 mmol) and amine (II, 0.19 g, 0.68 mmol) in dry methanol (10 mL) and dichloromethane (10 mL), and the mixture was stirred at room temperature for 16 hours. . To this was added MP-cyanoborohydride resin (0.46 g, 1.14 mmol) and stirred at room temperature for another 15 minutes. The reaction mixture was filtered and concentrated to remove methanol. The residue was diluted with dichloromethane (50 mL), it was washed with 10% NaHCO ₃ solution. The organic layer was dried over Na ₂ SO _4, and concentrated to give the crude product. The crude was purified by preparative HPLC to give Example 16 as a cloudy white solid (0.026 g, 10%). LC_MS calculated for C ₂₂ H ₂₂ FN ₅ O ₆ = 471.45; observed 472.0 [M + H] ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.22 (brs, 1H), 8.67 (brs, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.37-7.32 (m, 2H), 4.80-4.78 (m, 1H), 4.63 (s, 2H ), 4.28-4.24 (m, 1H), 3.79-3.75 (m, 1H), 3.31 (s, 3H), 3.20-3.14 (m, 4H), 2.98-2.96 (m, 2H), 2.12-2.10 (m , 2H).

(Example 17)
6- (5- (3-(((6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridin-7-yl) methyl) amino) propyl ) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one

Step 1: To a stirred solution of IIIg (1 g, 3.40 mmol) in DCM (20 mL) cooled to 0 ° C. was added Dess-Martin periodinane (2.16 g, 5.11 mmol) and stirred at rt for 2 h. The reaction mixture was carefully quenched with NaHCO ₃ solution (10 mL). The organic layer was separated, washed with sodium thiosulfate solution (2 × 25 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a colorless gummy solid of 17a. This was used without further purification in the next step (0.5 g, crude). LC_MS: calculated value of _{C 13 H 13 N 3 O 5} , 291.26, obs = 292.0

Step 2: To a mixture of XIII (0.20 g, 1.02 mmol) and aldehyde 17a (0.298 g, 1.02 mmol) in dry MeOH (6 mL) and DCM (6 mL) was added AcOH (0.20 mL) and stirred for 16 hours . To this was added sodium cyanoborohydride resin (0.843 g, 2.04 mmol) and stirred for 15 minutes. The reaction mixture was filtered and concentrated. The crude was purified by column chromatography (230/400 mesh, 7% DCM in MeOH) to give the desired compound, Example 17, as a white solid (40 mg, 12%). LC_MS calculated value of _{C 22 H 23 FN 6 O 5} , 470.46; observed value ^{471.2; [M + + H]} ; HPLC purity = 94.20% (HPLC Column: Phenomenex Gemini-N × C18 ( 150 × 4.6) mm, 3μm, Mobile phase A: 10 mM NH4OAc in water, mobile phase B: acetonitrile); ¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.21 (s, 1H), 8.96 (s, br, 2H), 8.23 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.24-6.98 (m, 1H), 4.76 (s, br, 1H), 4.62 (s, 2H ), 4.45 (s, 2H), 4.25-4.20 (m, 1H), 3.76-3.70 (m, 3H), 3.40 (s, 3H), 3.17-3.13 (m, 2H), 1.81-1.75 (m, 4H) ).

(Example 18)
Biological activity
1. Antibacterial activity The compounds of formula I are interesting due to their strong antibacterial effects. The ability of the compounds of the invention disclosed herein to produce antimicrobial effects is demonstrated by the following minimum inhibitory concentration (MIC) protocol using an assay based on the following E. coli ATCC 25922, S. aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter. They can be evaluated for their ability to inhibit the growth of bacterial species such as Baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853, E. faecalis ATCC 29212 and E. faecalis ATCC 29212.

  The test bacteria are grown in Luria Bertani broth (HIMEDIA M1245), 25 grams of the powder are dissolved in 1000 ml of distilled water, and sterilized by autoclaving at 15 pounds pressure (121 ° C.) for 20 minutes. The sterility of the medium is checked by incubating at 37 ° C. for 48 hours.

Bacterial cultures stored at -80 ° C as a glycerol stock solution are subcultured on LB agar plates to obtain isolated colonies. A single colony of each strain is cultured in LB broth. The culture is incubated at 37 ° C at 200 rpm until an optical density (OD at 600 nm) of 0.8-1 is reached. This log phase culture is diluted with LB broth to a cell number of 5-8 × 10 ⁵ CFU / mL and used as inoculum for MIC experiments. The test compound is dissolved in dimethyl sulfoxide (DMSO) to a stock concentration of 4 mg / ml. A two-fold dilution series of this DMSO stock solution is prepared in rows A through H of a 96-well V-bottom microtiter plate. Transfer a volume of 3 μL of these dilutions to a 96-well flat bottom microtiter assay plate. Controls for monitoring the effects of DMSO and media sterility are included. Inoculate each well with 150 μL of the diluted culture described above. Plates are incubated overnight at 37 ° C. in a humidified incubator. The next morning, the plate is read at a wavelength of 600 nM using a spectrophotometer. The minimum inhibitory concentration (MIC) is defined as the well containing the minimum drug concentrate that shows no turbidity. Table 1 shows the antimicrobial activity (MIC) determined for typical gram-positive pathogens (Staphylococcus aureus, E. faecalis) and gram-negative pathogens (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and A. baumannii). Recorded in 1). Exemplary compounds belonging to Formula I have demonstrated potent antibacterial activity against both Gram-positive and Gram-negative pathogens.

2. Enzyme Inhibition Assay: for use in the inhibition of E. coli gyrase determining bacteria type II topoisomerases IC ₅₀ for supercoiled form, i.e. DNA gyrase and killing or growth of Gram-positive and Gram-negative bacteria by inhibiting Topo IV Or a stereoisomer thereof, a pharmaceutically acceptable salt, complex, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form thereof And pharmaceutically active derivatives.

  The present invention also provides evidence for the treatment of infections caused by both Gram-positive and Gram-negative bacteria by inhibition of bacterial topoisomerase using the E. coli DNA gyrase enzyme.

E. coli DNA gyrase higher coil formation assay procedure E. coli gyrase higher coil formation and its inhibition were assayed using a kit (K0001) purchased from Inpiralis, and a protocol (PMID: 2172086) was required. With some minor modifications. The compounds to be tested are incubated with a 30 μl volume of the reaction and 2.5 nM E. coli DNA gyrase in 3.2% DMSO for 10 minutes. Next, 60 ng of relaxed pBR322 plasmid DNA is added to start the reaction and continued at 37 ° C. for 45 minutes. The reaction mixture, Tris.HCl of 35mM (pH7.5), 24mM of KCl, spermidine 1.8 mM, 4 mM of MgCl _2, 2 mM of DTT, glycerol 6.5% (w / v), 0.1mg / mL of BSA, And 1 mM ATP. The reaction is then stopped by adding 0.75 μL of proteinase K (20 mg / mL) and 3 μL of 2% SDS and further incubating at 37 ° C. for 30 minutes. Thereafter, 4 μL of STEB (40% (w / v) sucrose, 100 mM Tris-HCl, pH 8, 1 mM EDTA, 0.5 mg / ml bromophenol blue) was added to form a higher-order coil of plasmid DNA / The relaxed forms were separated by agarose gel electrophoresis. Run on a 1% agarose gel at 1 V TAE (40 mM Tris, 20 mM acetic acid, 1 mM EDTA) at 4 V / cm for 3 hours. To visualize the DNA, the gel is stained with 0.7 μg / mL ethidium bromide for 10 minutes and excess dye is removed by washing several times with water. Use Quantity One software (Bio-rad Co.) by densitometry method, relaxed DNA was supercoiled form in each reaction by quantifying the gel images and determine the IC _50.

E. coli topoisomerase IV delinking assay procedureE. Coli topoisomerase IV delinking activity and its inhibition were assayed using a kit (D4002) purchased from Inpiralis, and the kit protocol was similar to the gyrase higher order coil formation assay. Was adapted with the necessary modifications. The compound to be tested was incubated with a 30 μl volume of the reaction and 5 nM E. coli poisomerase IV in 3.2% DMSO for 10 minutes. The reaction was started by adding 60 ng of kDNA and continued at 37 ° C. for 40 minutes. The final reaction mixture contains 40 mM Tris.HCl (pH 7.6), 100 mM potassium glutamate, 10 mM magnesium acetate, 10 mM DTT, 1 mM ATP, and 50 μg / ml albumin. The reaction was stopped by adding 0.75 μL of proteinase K (20 mg / mL) and 3 μL of 2% SDS, and further incubated at 37 ° C. for 30 minutes. Thereafter, 4 μL of STEB (40% (w / v) sucrose, 100 mM Tris-HCl, pH 8, 1 mM EDTA, 0.5 mg / ml bromophenol blue) was added, and the kDNA / small circular form was subjected to agarose gel electrophoresis. Separated by electrophoresis. 1% agarose gel was run for 3 hours at 4 V / cm in 1 × TAE (40 mM Tris, 20 mM acetic acid, 1 mM EDTA). To visualize DNA, the gel was stained with 0.7 μg / mL ethidium bromide for 10 minutes and excess dye was removed by washing several times with water. Using the Quantity One software (Bio-rad) according to the densitometry method, the kinetoplast DNA band in the wells of the gel and the dissociated ring that migrated to the gel in each of the reactants were quantified from the gel image. , to determine the IC _50.

  Representative examples belonging to Formula I were evaluated against E. coli DNA gyrase and Topo IV enzymes using a gel-based supercoil formation assay for gyrase inhibition and a decoupled ring assay for Topo IV inhibition. . The results for bacterial type II Topo isomerases (Gyrase and Topo IV) are presented in Table 2. The results presented in Table 2 show that compounds belonging to Formula I exert their antimicrobial activity by inhibiting bacterial type II topoisomerase activity and represent a dual mechanism of inhibition with respect to the observed antimicrobial activity of the compound. It is shown that.

MIC ₅₀ and MI ₉₀ studies using clinical strains To test whether compounds from the series can retain antimicrobial activity against clinical strains of bacteria, antimicrobial susceptibility studies (MIC ₅₀ and MIC ₉₀ determinations) ) Was performed on a representative compound from a series (Example 14) using clinical strains of four Gram-negative bacterial species (E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and A. baumannii) according to standard CLSI guidelines. And the results are presented in FIG. 1 and Table 3. The standard drugs ciprofloxacin and meropenem were positive controls in this study.

The results presented in Table 3 and Figure 1 show that the compounds belonging to Formula I act on both drug-sensitive and drug-resistant clinical strains of Gram-negative bacteria and retain their antibacterial activity. Is shown. The MIC ₉₀ values of Example 14 range from 0.5 to 4 μg / ml for the four bacterial species and are found to be superior compared to the standard drug used in the study.

Mouse in vivo pharmacokinetic profile of Example 13 To evaluate the oral and intravenous pharmacokinetic profiles of Example 13, the pharmacokinetics (PK) of Example 13 were tested in BALB / c mice at a single dose of 2 mg / kg each. Characterized after intravenous (iv) administration and a single escalating oral dose of 2, 10, 50 and 100 mg / kg. This study was performed according to all Codes of Ethics as set forth in the Guidelines for Animal Welfare (Accession No. 1852 / PO / Rc / S / 16 / CPCSEA). This study was approved by the institutional Animals Ethics Committee (IAEC) of the testing facility. The formulations used for IVPK in BALB / c mice were DMSO: PEG400: ethanol: water (10: 20: 10: 60 v / v) and Example 13 administered as a solution. The formulations used for POPK were 0.1% Tween 80 in 0.25% CMC and Example 13 administered as a suspension by oral gavage. Plasma (mouse) samples were analyzed by LC-MS / MS. PK parameters were estimated by non-compartmental analysis in Phoenix WinNonlin 6.4. The results of the oral and intravenous PK studies of Example 13 are presented in Table 4 and Table 5.

After a single iv dose of 2.0 mg / kg in BALB / c mice, Example 13 shows a high systemic clearance [5.7 L / h / kg], a very high distribution volume at steady state [13.3 L / kg], and 1.7 It showed a medium t _1/2 of time. After a single oral dose of 2, 10, 50 and 100 mg / kg in BALB / c mice, AUC _0-∞ ranges between 0.07 to 4.82 μg.h / ml and C _max is 0.004 to 0.072 μg. / ml, and t _1/2 ranged between 1.4 and 5.6 hours. Oral bioavailability was moderate, ranging between 19-27%.

AUC _0-∞ increased linearly with dose [r ² = 0.9914] [AUC / dose ranges from 0.036 to 0.048]. C _max also increased linearly with doses of 10-100 mg / kg [C _max / dose ranges from 0.011 to 0.024].

In Vivo Efficacy in the Mouse E. coli Thigh Model To evaluate oral efficacy, Example 13 was tested once in a BALB / c mouse thigh infection model at 100 mg / kg over a 24-hour period after infection. , Once and twice at 50 mg / kg, three times at 33 mg / kg and four times at 25 mg / kg. This study was performed according to all Codes of Ethics as set forth in the Guidelines for Animal Welfare (Accession No. 1852 / PO / Rc / S / 16 / CPCSEA). This study was approved by the institutional Animals Ethics Committee (IAEC) of the testing facility. The formulations used were 0.1% Tween 80 in 0.25% CMC and Example 13 administered as a suspension by oral gavage. Neutropenic mice were infected with [約 1 × 10 ⁶ CFU / mouse] of E. coli [ATCC25922] by the intramuscular route. Two hours post-infection, mice were dosed for 24 hours in Example 13, with a total dose of 100, 50, 50, 33 and 25 mg / kg, as 1, 2, 3 and 4 doses evenly divided Orally for a period of time. Animals were sacrificed 24 hours after infection and thigh tissue was collected and bacterial CFU counts enumerated. The thigh muscle was placed in 1 ml of sterile LB broth and homogenized using a homogenizer (Omni Tip (220 volt portable)). Serial 10-fold dilutions of the thigh homogenate were prepared in sterile LB broth and 0.05 ml of the four dilutions per thigh were plated on lactose agar plates. Bacterial colonies were enumerated on each plate after approximately 20 hours incubation at 37 ° C. to determine bacterial density per thigh. Bacterial density Log10 CFU / mean ± SD of thigh was estimated for each group. Means of treatment groups were compared to the corresponding vehicle group using one-way analysis of variance with a 95% confidence level. P <0.05 was considered significant. The average Log10CFU / femur reduction after 24 hours of treatment compared to the 2 hour infected control was estimated for each group. The results of the efficacy study are presented in FIG.

  Example 13 demonstrates the significant efficacy of administering 1, 2, 3 and 4 doses of 100 mg / kg evenly divided while a single dose of 50 mg / kg , Was found to be ineffective.

Advantages As described in this subject matter and its equivalents, the foregoing embodiments have many advantages, including the aforementioned advantages.

  The compounds of the present disclosure exhibit high antibacterial activity against various pathogens, including Gram-positive and Gram-negative bacteria, by inhibiting bacterial topoisomerase via a novel mechanism.

  Although the subject matter has been described in considerable detail with reference to certain specific embodiments thereof, other embodiments are possible. Therefore, the spirit and scope of the invention should not be limited to the description of the embodiments contained herein.

Claims (14)

Compound of formula I
Or a salt, hydrate, solvate, tautomer, La Semi mixture and in optically active form state [formula a stereoisomer, pharmaceutically acceptable salt,
R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, and C ₃ -C ₆ cycloalkyl, each of which is unsubstituted or halogen, amino, hydroxy, Oxetane, -OC _1-6 alkyl, C _3-6 cycloalkylamino, C _1-6 alkylamino or di (C _1-6 alkyl) amino substituted with 1-3 groups independently selected. ,
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC _1-6 alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, halogen, and C _1-6 alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, is selected from halogen, cyano, -OC _{1 to 6} alkyl, -OC _{1 to 6} haloalkyl, and from the group consisting of C _{1 to 6} alkyl,
Y ₂ is N or CH;
Y ₃ is N or CR ₆ ,
R ₆ is hydrogen, is selected from halogen, cyano, C _{1 to 6} alkyl, -OC _{1 to 6} from the group consisting of alkyl and -OC _{1 to 6} haloalkyl,
When Z ₂ is C _1-6 alkylene, Z ₁ is NH, or when Z ₂ is NH, Z ₁ is C _1-6 alkylene;
n is 1 or 2,
W is CH _2, where the dotted line (----) represents a non-binding, if the dotted line (----) represents either bound or unbound, W is O ,
Ring A is
Selected from the group consisting of: R ₁ is hydrogen, C _{1 to 6} alkyl are selected from C _{2 to 6} alkenyl, and C ₃ -C ₆ group consisting of cycloalkyl, wherein alkyl, fluorine, hydroxy, amino, oxetane, -OC ₁ Optionally substituted with 1-3 groups independently selected from alkyl, _C3-6 cycloalkylamino, _C1-2 alkylamino, or di ( _C1-2 alkyl) amino;
R ₂ is selected from the group consisting of hydrogen, hydroxyl, and amino;
X is -NH, -NC ₁ alkyl, O, or CR ₃ R ₄ ,
R ₃ and R ₄ are independently selected from the group consisting of hydrogen, fluorine, and C ₁ alkyl;
Y ₁ is N or CR ₅ ;
R ₅ is hydrogen, fluorine, chlorine, cyano, -OCH _3, is selected from -OCF _3, OCHF _2, and the group consisting of C ₁ alkyl,
Y ₂ is N or CH,
Y ₃ is N or CR ₆ ;
R ₆ is hydrogen, fluorine, cyano, -OCH _3, is selected from the group consisting of -OCHF _2, and -OCF _3,
When Z ₂ is CH ₂ , Z ₁ is NH, or when Z ₂ is NH, Z ₁ is CH ₂ , CH ₂ CH ₂ or CH (OH) CH ₂ ;
n is 1 or 2,
When the dotted line (----) represents either a bond or a non-bond, W is O,
Ring A is
Selected from the group consisting of
A compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salts, hydrates, solvates, tautomers, La Semi mixtures and optically active form state. 6- (5- (2-(((1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-(((6-fluoro-1,3,3-trimethyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H -Pyrido [3,2-b] [1,4] oxazin-3 (4H) -one,
5- (5- (2-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2-methylnicotino Nitrile,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (3-(((1-ethyl-6-fluoro-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1),
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3 , 2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -one,
6- (5- (3-(((6-fluoro-1-methyl-2-oxoindoline-7-yl) methyl) amino) propyl) -2-oxooxazolidin-3-yl) -2H-benzo [b ] [1,4] oxazine-3 (4H) -one,
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 1),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindolin-7-yl) ethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (enantiomer 2),
6- (5- (2-((2- (6-fluoro-1-methyl-2-oxoindoline-7-yl) -2-hydroxyethyl) amino) ethyl) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one,
6- (5- (2-((2- (5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-4-yl) ethyl) amino) ethyl) -2-oxo Oxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, and
6- (5- (3-(((6-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b] pyridin-7-yl) methyl) amino) propyl The formula of claim 1, wherein the formula is selected from the group consisting of:) -2-oxooxazolidin-3-yl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one. compounds of I, or a stereoisomer, pharmaceutically acceptable salts, hydrates, solvates, tautomers, La semi mixtures and optically active form state. In the presence of AcOH and NaCNBH ₃ resin, the formula
Of the formula
By reacting with a compound of the formula I,
Or a stereoisomer, pharmaceutically acceptable salts, hydrates, methods of preparing solvates, tautomers, La Semi mixture and optically active form state. For use as a medicament, the compound according to any one of claims 1 to 3 or a stereoisomer thereof, a pharmaceutically acceptable salt , hydrate, solvate, tautomer , la semi mixtures and optically active form state. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, for use in killing or inhibiting the growth of a microorganism selected from the group consisting of bacteria, viruses, fungi, and protozoa, pharmaceuticals. acceptable salts, hydrates, solvates, tautomers, La semi mixtures and optically active form state. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection caused by a Gram-positive or Gram-negative bacterium. , hydrates, solvates, tautomers, La semi mixtures and optically active form state. Compound including a composition for treating a bacterial infection in a subject according to any one of claims 1 effective amount 3. 9. The composition of claim 8, wherein the bacterial infection is caused by a Gram-positive or Gram-negative pathogen. 10. The composition of claim 9, wherein the bacterial infection is caused by E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, A. baumannii, S. aureus, E. faecium, or E. faecium. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, for use in treating a disease or condition of a patient caused by a microorganism selected from the group consisting of a Gram-positive pathogen and a Gram-negative pathogen. , pharmaceutically acceptable salts, hydrates, solvates, tautomers, La semi mixtures and optically active form state. Bacteria, viruses, for inhibiting to order or growth kill microorganism selected from the group consisting of fungi and protozoa, compounds of formula I according to any one of claims 1 to 3, or a stereoisomer isomers, pharmaceutically acceptable salts, hydrates, solvates, tautomers, La semi mixtures and optically composition comprising an active form state. Compounds of formula I according to any one of claims 1 to 3, or a stereoisomer, pharmaceutically acceptable salts, hydrates, solvates, tautomers, La Semi mixture and optically active form state, including association with a pharmaceutically acceptable carrier, a pharmaceutical composition. Compounds of formula I according to any one of claims 1 to 3, or a stereoisomer, pharmaceutically acceptable salts, hydrates, solvates, tautomers, La Semi mixture and optically active form state, together with a pharmaceutically acceptable carrier, in combination with at least one antibiotic, a pharmaceutical composition.